Constrained compounds as CGRP-receptor antagonists

ABSTRACT

The invention encompasses constrained bicyclic and tricyclic CGRP-receptor antagonists, methods for identifying them, pharmaceutical compositions comprising them, and methods for their use in therapy for treatment of migraine and other headaches, neurogenic vasodilation, neurogenic inflammation, thermal injury, circulatory shock, flushing associated with menopause, airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), and other conditions the treatment of which can be effected by the antagonism of CGRP-receptors

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is continuation-in-part of U.S. nonprovisionalapplication Ser. No. 11/247,697, filed Oct. 11, 2005, and claims thebenefit of U.S. provisional application Ser. Nos. 60/624,655 filed Nov.3, 2004 and U.S. provisional application 60/678,099 filed May 5, 2005.

BACKGROUND OF THE INVENTION

Calcitonin gene-related peptide (CGRP) is a naturally occurring37-amino-acid peptide first identified in 1982 (Amara, S. G. et al,Science 1982, 298, 240-244). Two forms of the peptide are expressed(αCGRP and βCGRP) which differ by one and three amino acids in rats andhumans, respectively. The peptide is widely distributed in both theperipheral (PNS) and central nervous system (CNS), principally localizedin sensory afferent and central neurons, and displays a number ofbiological effects, including vasodilation.

When released from the cell, CGRP binds to specific cell surface Gprotein-coupled receptors and exerts its biological action predominantlyby activation of intracellular adenylate cyclase (Poyner, D. R. et al,Br J Pharmacol 1992, 105, 441-7; Van Valen, F. et al, Neurosci Lett1990, 119, 195-8.). Two classes of CGRP receptors, CGRP₁ and CGRP₂, havebeen proposed based on the antagonist properties of the peptide fragmentCGRP(8-37) and the ability of linear analogues of CGRP to activate CGRP₂receptors (Juaneda, C. et al. TiPS 2000, 21, 432-438). However, there islack of molecular evidence for the CGRP₂ receptor (Brain, S. D. et al,TiPS 2002, 23, 51-53). The CGRP₁ receptor has three components: (i) a 7transmembrane calcitonin receptor-like receptor (CRLR); (ii) the singletransmembrane receptor activity modifying protein type one (RAMP1); and(iii) the intracellular receptor component protein (RCP) (Evans B. N. etal., J Biol Chem. 2000, 275, 31438-43). RAMP1 is required for transportof CRLR to the plasma membrane and for ligand binding to theCGRP-receptor (McLatchie, L. M. et al, Nature 1998, 393, 333-339). RCPis required for signal transduction (Evans B. N. et al., J Biol Chem.2000, 275, 31438-43). There are known species-specific differences inbinding of small molecule antagonists to the CGRP-receptor withtypically greater affinity seen for antagonism of the human receptorthan for other species (Brain, S. D. et al, TiPS 2002, 23, 51-53). Theamino acid sequence of RAMP1 determines the species selectivity, inparticular, the amino acid residue Trp74 is responsible for thephenotype of the human receptor (Mallee et al. J Biol Chem 2002, 277,14294-8).

Inhibitors at the receptor level to CGRP are postulated to be useful inpathophysiologic conditions where excessive CGRP receptor activation hasoccurred. Some of these include neurogenic vasodilation, neurogenicinflammation, migraine, cluster headache and other headaches, thermalinjury, circulatory shock, menopausal flushing, and asthma. CGRPreceptor activation has been implicated in the pathogenesis of migraineheadache (Edvinsson L. CNS Drugs 2001; 15(10):745-53; Williamson, D. J.Microsc. Res. Tech. 2001, 53, 167-178.; Grant, A. D. Brit. J. Pharmacol.2002, 135, 356-362.). Serum levels of CGRP are elevated during migraine(Goadsby P J, et al. Ann Neurol 1990;28:183-7) and treatment withanti-migraine drugs returns CGRP levels to normal coincident withalleviation of headache (Gallai V. et al. Cephalalgia 1995;15: 384-90).Migraineurs exhibit elevated basal CGRP levels compared to controls(Ashina M, et al., Pain 2000, 86(1-2): 133-8.2000). Intravenous CGRPinfusion produces lasting headache in migraineurs (Lassen L H, et al.Cephalalgia February 2002;22(1):54-61). Preclinical studies in dog andrat report that systemic CGRP blockade with the peptide antagonistCGRP(8-37) does not alter resting systemic hemodynamics nor regionalblood flow (Shen, Y-T. et al, J Pharmacol Exp Ther 2001, 298, 551-8).Thus, CGRP-receptor antagonists may present a novel treatment formigraine that avoids the cardiovascular liabilities of activevasoconstriction associated with non-selective 5-HT_(1B/1D) agonists,‘triptans’ (e.g., sumatriptan).

A number of non-peptidic, small molecule CGRP-receptor antagonists havebeen recently reported. WO 04/091514, WO 04/092166 and WO 04/092168disclose cyclic compounds containing an amide bond in the ring as CGRPantagonists. WO 97/09046 and equivalents disclose inter alia quinine andquinidine related compounds which are ligands, in particularantagonists, of CGRP-receptor. WO 98/09630 and WO 98/56779 andequivalents disclose inter alia variously substituted, nitrobenzamidecompounds as CGRP-receptor antagonists. WO 01/32649, WO 01/49676, and WO01/32648 and equivalents disclose inter alia a series of4-oxobutanamides and related cyclopropane derivatives as CGRP-receptorantagonists. WO 00/18764, WO 98/11128 and WO 00/55154 and equivalentsdisclose inter alia benzimidazolinyl piperidines as antagonists toCGRP-receptor. Unrelated to CGRP, a series of somatostatin antagonistshave been disclosed in WO 99/52875 and WO 01/25228 and equivalents. Seealso U.S. Pat. No. 6,344,449, U.S. Pat. No. 6,313,097, U.S. Pat. No.6,521,609, U.S. Pat. No. 6,552,043, US 20030181462, US20030191068 and WO03/076432 and related applications. Thus, novel CGRP-receptorantagonists effective for the treatment of neurogenic inflammation,migraine and other disorders would be greatly advantageous.

DESCRIPTION OF THE INVENTION

The invention encompasses compounds of Formula I and II which are CGRPantagonists. The invention also encompasses compositions incorporatingthese compounds and methods of using these compounds in therapeutictreatment.

One aspect of the invention is a compound of Formula I

wherein:

-   R¹ is C₁₋₆alkyl, C₂₋₆alkenyl, C₃₋₇cycloalkyl, C₅₋₇cycloalkenyl,    C₁₋₆(C₃₋₇cycloalkyl)alkyl, C₁₋₆haloalkyl, C₁₋₆(C₁₋₆alkoxy)alkyl,    C₁₋₆(Ar¹)alkyl, C₁₋₆(NR⁷R⁸)alkyl, N—(R⁹)-pyrrolidinyl or    N—(R⁹)-piperidinyl;-   R² is hydrogen, halo, hydroxy, C₁₋₆alkyl, C₂₋₆alkenyl, benzyloxy, or    NR⁷R⁸;-   R³ is hydrogen, hydroxy, halo, C₁₋₆alkyl, or C₂₋₆alkenyl;-   or R² and R³ taken together are CHNNR⁵;-   R⁴ is hydrogen, halo or C₁₋₆alkyl, or C₂₋₆alkenyl;-   R⁵ is hydrogen or C₁₋₆alkyl;-   R⁶ is hydrogen, C₁₋₆alkyl,

-   or NR⁵R⁶ taken together is

-   R⁷ is hydrogen or C₁₋₆alkyl;-   R⁸ is hydrogen or C₁₋₆alkyl; or-   NR⁷R⁸ taken together is selected from the group consisting of    pyrrolidinyl, piperidinyl, N—(R⁹)-piperazinyl, morpholinyl, and    thiomorpholinyl;-   R⁹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl, or C₁₋₆alkoxycarbonyl;-   R¹⁰ is phenyl, naphthyl, pyridinyl, pyridinyl N-oxide, quinolinyl,    quinolinyl N-oxide, isoquinolinyl, or isoquinolinyl N-oxide, and is    substituted with 0-2 substituents selected from the group consisting    of halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, hydroxy, and phenyl;-   or R¹⁰ is selected from the group consisting of

-   R¹¹ is hydrogen, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkoxy;-   Ar¹ is phenyl, naphthyl, pyridinyl, or imidazolyl, and is    substituted with 0-2 substituents selected from the group consisting    of halo, C₁₋₆alkyl, and C₁₋₆haloalkyl;-   Ar² is phenyl, naphthyl, or pyridinyl, and is substituted with 0-2    substituents selected from the group consisting of halo, C₁₋₆alkyl,    and C₁₋₆haloalkyl;-   X—Y is aminocarbonyl, oxycarbonyl, methylenecarbonyl, ethylene, or    amino(cyano)iminomethyl;-   Z is N or CH; and-   n is 0 or 1;-   or a pharmaceutically acceptable salt or solvate thereof.

Another aspect of the invention is a compound of Formula Ia.

Another aspect of the invention is a compound of Formula Ib.

Another aspect of the invention is a compound of Formula II.

Another aspect of the invention is a compound of Formula IIa.

Another aspect of the invention is a compound of Formula IIb.

Another aspect of the invention is a compound of Formula I or II whereR⁴ is chloro, fluoro, or methyl.

Another aspect of the invention is a compound of Formula I or II whereNR⁵R⁶ taken together is

Another aspect of the invention is a compound of Formula I or II whereNR⁵R⁶ taken together is

Another aspect of the invention is a compound of Formula I or II whereR¹⁰ is selected from the group consisting of

Another aspect of the invention is a compound of Formula I or II whereR¹¹ is hydrogen, chloro, fluoro, or methyl.

Another aspect of the invention is a compound of Formula I or II where Zis CH.

Another aspect of the invention is a compound of Formula I where n is 1.

Another aspect of the invention is that any scope of variables R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, Ar¹, Ar², X—Y, Z, and n can beused with any scope of the remaining variables.

“Alkyl,” “hydroxyalkyl,” “alkoxy” and related terms with an alkyl moietyinclude straight and branched isomers. “Alkenyl” means a straight orbranched alkyl group with at least one double bond. A term such asC₁₋₆(R)alkyl means a straight or branched alkyl group of one to sixcarbons substituted with the substituent R. A term such asN—(R)-pyrrolidinyl indicates that the nitrogen is substituted with thesubstituent R. “Haloalkyl” and “haloalkoxy” include all halogenatedisomers from monohalo substituted alkyl to perhalo substituted alkyl.“Aryl” includes carbocyclic and heterocyclic aromatic ring systems.“Amino” includes includes primary, secondary, and tertiary moieties.“Carbonyl” means CO. “Oxy” means —O—. “Aminocarbonyl” means —N(R)C(═O)—.“Oxycarbonyl” means —OC(═O)—. “Methylenecarbonyl” means —CH₂C(═O)—.“Amino(cyano)iminomethyl” means —NHC(═NCN)—.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

The invention also includes all solvated forms of the compounds,particularly hydrates. Solvates do not contribute significantly to thephysiological activity or toxicity of the compounds and as such functionas pharmacological equivalents. Solvates may form in stoichiometricamounts or may form from adventitious solvent or a combination of both.One type of solvate is hydrate, and some hydrated forms includemonohydrate, hemihydrate, and dihydrate.

Some compounds of the invention may exist in stereoisomeric forms, oneexample of which is shown below. The invention includes allstereoisomeric and tautomeric forms of the compounds.

Synthetic Methods

The compounds described in the present invention can be synthesizedaccording to Schemes 1-4 as well as other procedures known in the art.Starting materials are commercially available or synthesized by commonsynthetic procedures. Variations of the compounds and the procedures tomake them which are not illustrated are within the skill of the art.

Scheme 1 describes how to make certain compounds of the invention.Regiospecific introduction of iodine on a appropriately substitutedaromatic ring can be accomplished using iodine monochloride. Aryliodides (II) are good coupling partners in palladium-mediated Heckreactions. The Heck products (III) can be reduced with hydrogen mediatedby number of asymmetric catalysts to produce enatiomerically purematerials (IV). Subsequent hydrolysis of acetate functionality withmethanolic potassium carbonate followed by treatment of alcohol (V) withthionyl chloride can produce benzylic chlorides (VI). Treatment ofbenzylic chlorides with various amines in acetonitrile can deliverrequisite amines (VII).

The amines (VII) can be converted into desired azepinones (VIII) inrefluxing toluene mediated by catalytic acetic acid. The azepinoneintermediates VIII (X═NH, CH₂, O) can in turn be elaborated into finalproducts. Hydrogenolysis of VIII (X═NH) under 10% Pd on carbon producesamine intermediate IX (Scheme II). The amine functionality can betransformed to the desired urea functionality (X) with the assistance ofphosgene or N,N′-disuccinimyl dicarbonate and various amines (Scheme 2).Alternatively, the succinic ester VIII (X═CH₂) can be converted tocarboxylic acid (XI) with lithium hydroxide, followed by reaction withan appropriate amine under TBTU coupling conditions to give desiredamides (XII) (Scheme 3).

In a manner similar to urea formation, cyanoguanidine XIII can beprepared using diphenyl N-cyanocarboimidate and various substitutedamines (Scheme 4).

Biological Methods

CGRP Binding Assay. Tissue Culture. SK—N-MC cells were grown at 37° C.in 5% CO₂ as a monolayer in medium consisting of MEM with Earle's saltsand L-glutamine (Gibco) supplemented with 10% fetal bovine serum(Gibco). Cell Pellets. The cells were rinsed twice withphosphate-buffered saline (155 mM NaCl, 3.3 mM Na₂HPO₄, 1.1 mM KH₂PO₄,pH 7.4), and incubated for 5-10 min. at 4° C. in hypotonic lysis bufferconsisting of 10 mM Tris (pH 7.4) and 5 mM EDTA. The cells weretransferred from plates to polypropylene tubes (16×100 mm) andhomogenized using a polytron. Homogenates were centrifuged at 32,000×gfor 30 min. The pellets were resuspended in cold hypotonic lysis bufferwith 0.1% mammalian protease inhibitor cocktail (Sigma) and assayed forprotein concentration. The SK—N-MC homogenate was then aliquoted andstored at −80° C. until needed.

Radioligand Binding Assay. The compounds of invention were solubilizedand carried through serial dilutions using 100% DMSO. Aliquots from thecompound serial dilutions were further diluted 25 fold into assay buffer(50 mM Tris-Cl pH 7.5, 5 mM MgCl₂, 0.005% Triton X-100) and transferred(volume 50 μl) into 96 well assay plates. [¹²⁵I]-CGRP (AmershamBiosciences) was diluted to 60 pM in assay buffer and a volume of 50 μlwas added to each well. SK—N-MC pellets were thawed, diluted in assaybuffer with fresh 0.1% mammalian protease inhibitor cocktail (Sigma),and homogenized again. SK—N-MC homogenate (5 μg/well) was added in avolume of 100 μl. The assay plates were then incubated at roomtemperature for 2 h. Assays were stopped by addition of excess cold washbuffer (20 mM Tris-Cl pH 7.5, 0.1% BSA) immediately followed byfiltration over glass fiber filters (Whatman GF/B) previously soaked in0.5% PEI. Non-specific binding was defined with 1 μM beta-CGRP. Proteinbound radioactivity was determined using a gamma or scintillationcounter. The IC₅₀ was defined as the concentration of a compound ofinvention required to displace 50% of radioligand binding.

Cyclic AMP Functional Antagonism Assay. Antagonism of the compounds ofinvention was determined by measuring the formation of cyclic AMP(adenosine 3′5′-cyclic monophosphate) in SK—N-MC cells that endogenouslyexpress the human CGRP receptor. CGRP receptor complex is coupled withGs protein and CGRP binding to this complex leads to the cyclic AMPproduction via Gs—dependent activation of an adenylate cyclase (JuanedaC et al., TiPS, 2000; 21:432-438; incorporated by reference herein).Consequently, CGRP receptor antagonists inhibit CGRP—induced cyclic AMPformation in SK—N-MC cells (Doods H et al., Br J Pharmacol, 2000;129(3):420-423) ; incorporated by reference herein). For cyclic AMPmeasurements SK—N-MC cells were incubated with 0.3 nM CGRP alone or inthe presence of various concentrations of the compounds of invention for30 min at room temperature. Compounds of invention were pre-incubatedwith SK—N-MC cells for 15 min before the addition of CGRP to allowreceptor occupancy (Edvinsson et al., Eur J Pharmacol, 2001, 415:39-44;incorporated by reference herein). Cyclic AMP was extracted using thelysis reagent and its concentration was determined by radioimmunoassayusing RPA559 cAMP SPA Direct Screening Assay Kit (Amersham PharmaciaBiotech). IC50 values were calculated using Excel fit. The testedcompounds of the invention were determined to be antagonists as theyexhibited a does—dependent inhibition of the CGRP—induced cyclic AMPproduction.

In the Table 4, results are denoted as follows: A 0.1-10 nM; B=10-100nM; C=100-1000 nm; D>1000 nM.

TABLE 4 CGRP Binding and cAMP Functional Data CGRP binding¹ cAMPFunction² Example IC₅₀ (nM) IC₅₀ (nM) 1 B B 2 C * 3 C * 4 C * 5 C * 6 BB 7 B * 8 D * 9 C * 10 B B 11 B B 12 A A 13 B * 14 C * 15 B * 16 A A 17B * 18 C * 19 B A 20 A A 21 A A 22 A A 23 B * 24 B B 25 C * 26 A A 27C * 28 B B 29 C * 30 B B 31 D * 32 C * 33 D * 34 C * 35 B * 36 B B 37 AB 38 C * 39 B B 40 A A 41 A A 42 B B 43 A A 44 A A 45 A A 46 A A 47 B B48 B * 49 A A 50 A A 51 A * 52 A A 53 A A 54 A A 55 C * 56 C * 57 C * 58C * 59 C * 60 D * 61 D * 62 B * 63 C * 64 D * 65 D * 66 B * 67 B * 68C * 69 B * 70 C * 71 C * 72 D * 73 D * 74 D * 75 A * 76 B * 77 B * 78A * 79 A * 80 B B 81 B * 82 A * 83 C * 84 C * 85 B B 86 A * 87 B * 88A * 89 A * 90 A * 91 A * 92 B * 93 C * 94 A * 95 B * 96 A * 97 A * 98B * 99 A * 100 A * 101 B * 102 A * 103 B * 104 B * 105 B * 106 B * 107C * 108 B * 109 C * 110 B * 111 A * 112 B * 113 A * 114 B * 115 B * 116A * 117 C * 118 B * 119 D * 120 A *

Pharmaceutical Compositions and Methods of Treatment

The compounds of Formula I inhibit the CGRP receptor. As such, they areuseful for treating disorders associated with aberrant CGRP levels orwhere modulating CGRP levels may have therapeutic benefit.

Accordingly, another aspect of the invention is a pharmaceuticalcomposition comprising a compound of Formula I with a pharmaceuticallyacceptable adjuvant, carrier, or diluent.

Compounds are generally given as pharmaceutical compositions comprisedof a therapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt, and a pharmaceutically acceptablecarrier and may contain conventional exipients. A therapeuticallyeffective amount is the amount needed to provide a meaningful patientbenefit as determined by practitioners in that art. Pharmaceuticallyacceptable carriers are those conventionally known carriers havingacceptable safety profiles. Compositions encompass all common solid andliquid forms including capsules, tablets, losenges, and powders as wellas liquid suspensions, syrups, elixers, and solutions. Solidcompositions may by formed in timed or sustained released formulations.Compositions are made using common formulation techniques andconventional excipients (such as binding and wetting agents) andvehicles (such as water and alcohols).

Solid compositions are normally formulated in dosage units providingfrom about 1 to about 1000 mg of the active ingredient per dose. Someexamples of solid dosage units are 0.1 mg, 1 mg, 10 mg, 100 mg, 500 mg,and 1000 mg. Liquid compositions are generally in a unit dosage range of1-100 mg/mL. Some examples of liquid dosage units are 0.1 mg/mL, 1mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.

The invention encompasses all conventional modes of administrationincluding oral, parenteral, intranasal, sublingual, and transdermalmethods. Typically, the daily dose will be 0.01-100 mg/kg body weightdaily. Generally, more compound is required orally and lessparenterally. The specific dosing regime, however, should be determinedby a physician using sound medical judgement.

Inhibitors at the receptor level to CGRP are postulated to be useful inpathophysiologic conditions where excessive CGRP receptor activation hasoccurred. Some of these include neurogenic vasodilation, neurogenicinflammation, migraine, cluster headache and other headaches, thermalinjury, circulatory shock, menopausal flushing, and asthma. CGRPreceptor activation has been implicated in the pathogenesis of migraineheadache (Edvinsson L. CNS Drugs 2001, 15(10), 745-53; Williamson, D. J.Microsc. Res. Tech. 2001, 53, 167-178.; Grant, A. D. Brit. J. Pharmacol.2002, 135, 356-362.). Serum levels of CGRP are elevated during migraine(Goadsby P. J. et al. Ann. Neurol. 1990, 28, 183-7) and treatment withanti-migraine drugs returns CGRP levels to normal coincident withalleviation of headache (Gallai V. et al. Cephalalgia 1995, 15, 384-90).Migraineurs exhibit elevated basal CGRP levels compared to controls(Ashina M. et al., Pain 2000, 86(1-2), 133-8). Intravenous CGRP infusionproduces lasting headache in migraineurs (Lassen L. H. et al.Cephalalgia. 2002, 22(1), 54-61). Preclinical studies in dog and ratreport that systemic CGRP blockade with the peptide antagonistCGRP(8-37) does not alter resting systemic hemodynamics nor regionalblood flow (Shen, Y-T. et al. J Pharmacol. Exp. Ther. 2001, 298, 551-8).Thus, CGRP-receptor antagonists may present a novel treatment formigraine that avoids the cardiovascular liabilities of activevasoconstriction associated with non-selective 5-HT_(1B/1D) agonists,“triptans” (e.g., sumatriptan).

Another aspect of the invention is a method of treating migraine orheadache.

“Migraine,” “headache,” and related terms are as understood by medicalpractitioners. Migraine encompasses all classes of migraine includingcommon, classic, cluster, fulgurating, hemiplegic, opthalmoplegic, andopthomalmic.

“Therapeutically effective” means there is a meaningful patient benefitas understood by medical practitioners.

“Patient” means a person who may benefit from treatment as determined bymedical practitioners.

Another aspect of the invention relates to a method of treatinginflammation (particularly neurogenic inflammation), pain, thermalinjury, circulatory shock, diabetes, Reynaud's syndrome, peripheralarterial insufficiency, subarachnoid/cranial hemorrhage, tumor growth,flushing associated with menopause and other conditions the treatment ofwhich can be effected by the antagonism of the CGRP receptor by theadministration of pharmaceutical compositions comprising compounds ofFormula (I) as defined herein.

Another aspect of the invention relates to methods selected from thegroup consisting of (a) immune regulation in gut mucosa (b) protectiveeffect against cardiac anaphylactic injury (c) stimulating or preventinginterleukin-1b(IL-1b)-stimulation of bone resorption (d) modulatingexpression of NK1 receptors in spinal neurons and (e) airwayinflammatory diseases and chronic obstructive pulmonary diseaseincluding asthma. See (a) Calcitonin Receptor-Like Receptor Is Expressedon Gastrointestinal Immune Cells. Hagner, Stefanie; Knauer, Jens;Haberberger, Rainer; Goeke, Burkhard; Voigt, Karlheinz; McGregor, GerardPatrick. Institute of Physiology, Philipps University, Marburg, Germany.Digestion (2002), 66(4), 197-203; (b) Protective effects of calcitoningene-related peptide-mediated evodiamine on guinea-pig cardiacanaphylaxis. Rang, Wei-Qing; Du, Yan-Hua; Hu, Chang-Ping; Ye, Feng; Tan,Gui-Shan; Deng, Han-Wu; Li, Yuan-Jian. School of PharmaceuticalSciences, Department of Pharmacology, Central South University, Xiang-YaRoad 88, Changsha, Hunan, Naunyn-Schmiedeberg's Archives of Pharmacology(2003), 367(3), 306-311; (c) The experimental study on the effectcalcitonin gene-related peptide on bone resorption mediated byinterleukin-1. Lian, Kai; Du, Jingyuan; Rao, Zhenyu; Luo, Huaican.Department of Orthopedics, Xiehe Hospital, Tongji Medical College,Huazhong University of Science and Technology, Wuhan, Peop. Rep. China.Journal of Tongji Medical University (2001), 21(4), 304-307, (d)Calcitonin gene-related Peptide regulates expression of neurokinin1receptors by rat spinal neurons. Seybold V S, McCarson K E, MermelsteinP G, Groth R D, Abrahams L G. J. Neurosci. 2003 23 (5): 1816-1824.Department of Neuroscience, University of Minnesota, Minneapolis, Minn.55455, and Department of Pharmacology, Toxicology, and Therapeutics,University of Kansas Medical Center, Kansas City, Kans. 66160 (e)Attenuation of antigen-induced airway hyperresponsiveness inCGRP-deficient mice. Aoki-Nagase, Tomoko; Nagase, Takahide; Oh-Hashi,Yoshio; Shindo, Takayuki; Kurihara, Yukiko; Yamaguchi, Yasuhiro;Yamamoto, Hiroshi; Tomita, Tetsuji; Ohga, Eijiro; Nagai, Ryozo;Kurihara, Hiroki; Ouchi, Yasuyoshi. Department of Geriatric Medicine,Graduate School of Medicine, University of Tokyo, Tokyo, Japan. AmericanJournal of Physiology (2002), 283(5, Pt. 1), L963-L970; (f) Calcitoningene-related peptide as inflammatory mediator. Springer, Jochen;Geppetti, Pierangelo; Fischer, Axel; Groneberg, David A. ChariteCampus-Virchow, Department of Pediatric Pneumology and Immunology,Division of Allergy Research, Humboldt-University Berlin, Berlin,Germany. Pulmonary Pharmacology & Therapeutics (2003), 16(3), 121-130;and (g) Pharmacological targets for the inhibition of neurogenicinflammation. Helyes, Zsuzsanna; Pinter, Erika; Nemeth, Jozsef;Szolcsanyi, Janos. Department of Pharmacology and Pharmacotherapy,Faculty of Medicine, University of Pecs, Pecs, Hung. Current MedicinalChemistry: Anti-Inflammatory & Anti-Allergy Agents (2003), 2(2), 191-218all incorporated by reference herein.

Another aspect of this invention relates to a method of treatment usingcombinations of Formula I compounds with one or more agents selectedfrom the group consisting of COX-2 inhibitors, NSAIDS, aspirin,acetaminophen, triptans, ergotamine and caffeine for the treatment ofmigraine.

Description of Specific Embodiments

Proton magnetic resonance (1H NMR) spectra were recorded on a Bruker AC300 or AC 500. All spectra were determined in the solvents indicated andchemical shifts are reported in δ units downfield from the internalstandard tetramethylsilane (TMS) and interproton coupling constants arereported in Hertz (Hz). Splitting patterns are designated as follows: s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broadpeak. Low resolution mass spectra (MS) and the apparent molecular (MH+)or (M−H)+was determined on a Micromass platform. The elemental analysisare reported as percent by weight. The products were purified by PrepHPLC using the column YMC S5 ODS (30×100 mm) at a flow rate of 40.0mL/min and gradient time of 8.0 min. starting from solvent compositionof 40% MeOH-60% H2O-0.1% TFA and ending with solvent composition 95%MeOH-5% H2O-0.1% TFA. The products were analyzed by a HPLC instrumentusing an XTERA column (3.0×50 mm S7) starting from solvent A (10%MeOH-90% water-0.1% trifluoroacetic acid (TFA)) and reaching solvent B(10% water-90% methanol-0.1% TFA) over a gradient time of 2 min. Theflow rate is 5 mL/min. and retention time (Rf) of product was measuredat 220 nm wavelength.

2-(Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzylidene)-succinicacid diethyl ester. Nitrogen gas was bubbled through a solution ofacetic acid 3-tert-butoxycarbonylamino-6-iodo-2-methyl-benzyl ester(3.85 g, 9.5 mmol), itaconic acid diethyl ester (2.2 mL, 12 mmol),tetrabutylammonium chloride (3.4 g, 12 mmol), and triethylamine (4.0 mL,29 mmol) in N,N-dimethylformamide (25 mL) for 5 minutes. Palladium (II)acetate (0.32 g, 1.4 mmol) was added. Mixture was heated at 100° C. for45 minutes. Mixture was cooled to room temperature then diluted withdiethyl ether (100 ml). Mixture was washed successively with water (3×50mL), and brine (25 mL). Organic was dried (MgSO₄), filtered andconcentrated in vacuo. Silica gel purification yielded the desiredproduct in 99% yield as an amber oil. ¹H NMR (300 MHz, CDCl₃): δ=8.0 (s,1H), 7.78 (d, J=8.4, 1H), 7.08 (d, J=8.4, 1H), 6.32 (s, 1H), 5.11 (s,2H), 4.27 (q, J=7.3, 2H), 4.11 (q, J=7.1, 2H), 3.30 (s, 2H), 2.24 (s,3H), 2.04 (s, 3H), 1.55 (s, 3H), 1.51 (s, 9H), 1.32 (t, J=7.1, 3H), 1.23(t, J=7.3, 3H). MS m/e (M−H)⁻=462.0.

2-(S)-(Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester.2-(S)-(Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzylidene)-succinicacid diethyl ester (4.4 g, 9.5 mmol) and(−)-1,2-bis((2R,5R)-diethylphospholano)benzene(cyclooctadiene)rhodium(I) trifluoromethane sulfonate (100 mg) was dissolved in ethanol (80mL). Mixture was placed on a Parr hydrogenation apparatus. Reactionvessel was charged with 60 psi of hydrogen gas. Reaction mixture wasallowed to shake at room temperature for 18 hours. Reaction mixture wasconcentrated in vacuo. Residue was passed through a plug of silica geleluting 80% ethyl acetate-hexanes (250 mL). Filtrate was concentrated invacuo to afford the desired product in 97% yield as an amber oil. ¹H NMR(300 MHz, CDCl₃): δ=7.62 (d, J=8.1, 1H), 7.01 (d, J=8.4, 1H), 6.20 (s,1H), 5.20 (m, 2H), 4.09 (m, 4H), 3.14 (m, 1H), 2.69 (m, 2H), 2.38 (dd,J1=16.8, J2=4.8, 1H), 2.23 (s, 3H), 2.07 (s, 3H), 1.56 (3, 3H), 1.50 (s,9H), 1.22 (m, 6H). MS m/e (M−H)⁻=464.0.

2-(S)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethylester. Trifluoroacetic acid (10 mL) was added to a solution of2-(S)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester (4.6 g, 9.9 mmol) in dichloromethane (40 mL).Reaction mixture was stirred at room temperature for 1.5 hours. Mixturewas concentrated in vacuo. Residue was dissolved in dichloromethane (75mL) and washed successively with saturated aqueous sodium bicarbonate(2×50 mL) and brine (30 mL). Organic was dried (magnesium sulfate),filtered and concentrated in vacuo to yield the desired product in 99%yield as an amber oil. ¹H NMR (300 MHz, CDCl₃): δ=6.85 (d, J=8.1, 1H),6.67 (d, J=8.4, 1H), 5.18 (m, 2H), 4.09 (m, 4H), 3.09 (dd, J1=6.2,J2=13.9, 1H), 2.96 (m, 1H), 2.66 (m, 2H), 2.37 (dd, J1=4.6, J2=16.7,1H), 2.15 (s, 3H), 2.06 (s, 3H), 1.20 (m, 6H). MS m/e(M−C₂H₄O₂+H)⁺=306.2.

2-(S)-(4-Acetoxymethyl-1H-indazol-5-ylmethyl)-succinic acid diethylester. Isoamyl nitrite (1.6 mL, 12 mmol) was added dropwise to a cooled(water ice bath) sollution of2-(S)-(2-acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethylester in carbontetrachloride (80 mL) and acetic acid (4 mL). Mixture wasstirred at 0° C. for 2 hours. Mixture was warmed and stirred at ambienttemperature for 14 hours. Mixture was concentrated in vacuo. Residue wasdissolved in dichloromethane (75 mL) then washed successively withsaturated aqueous sodium bicarbonate (2×50 mL), and brine (30 mL).Organic was dried (magnesium sulfate), filtered and concentrated invacuo. Silica gel chromatography (ethyl acetate-hexanes) afforded theproduct in 55% yield as an amber oil. ¹H NMR (300 MHz, CDCl₃): δ=8.19(s, 1H), 7.44 (d, J=8.8, 1H), 7.24 (d, J=8.8, 1H), 5.49 (s, 2H), 4.06(m, 4H), 3.25 (m, 1H), 3.11 (m, 1H), 2.97 (m, 1H), 2.72 (dd, J1=8.8,J2=16.5, 1H) 2.43 (dd, J1=5.1, J2=16.5), 2.09 (s, 3H), 1.19 (m, 6H). MSm/e (M+H)⁺=377.1.

2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester. Potassium carbonate (1.6 g, 11.6 mmol) was added to a solution of2-(S)-(4-acetoxymethyl-1H-indazol-5-ylmethyl)-succinic acid diethylester (2.0 g, 5.5 mmol) in methanol (60 mL). Mixture was stirred at roomtemperature for 1.5 hours. Reaction was quenched with the addition of 1Nhydrochloric acid (30 mL). Methanol was removed from the mixture invacuo. Remaining aqueous was basified with sodium bicarbonate. Mixturewas extracted with ethyl acetate (2×40 mL). Combined organic layers werewashed successively with water (30 mL) and brine (30 mL). Organic wasdried (magnesium sulfate), filtered then concentrated in vacuo. Desiredproduct was obtained in 92% yield as an amber oil. ¹H NMR (300 MHz,CDCl₃): δ=8.21 ((s, 1H), 7.34 (d, J=9.2, 1H), 7.17 (d, J=8.8, 1H), 5.02(dd, J1=12.4, J2=17.9, 1H) 3.63 (s, 6H), 3.23 (m, 1H), 2.98 (m, 1H),2.77 (dd, J1=7.7, J2=16.8, 1H), 2.53 (dd, J1=6.4, J2=16.7, 1H). MS m/e(M+H)⁺=307.0.

2-(S)-(4-Chloromethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester hydrochoride. Thionyl chloride (5.0 mL) was added to a solution of2-(S)-(4-hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester (1.53 g, 5.0 mmol) in dichloromethane (30 mL). Reaction mixturewas stirred at ambient temperature for 2 hours. Mixture was concentratedin vacuo. Residue was triturated in toluene (30 mL), then concentratedin vacuo. Residue was treated with dichloromethane (30 mL) thenconcentrated in vacuo. Desired product was obtained in 96% yield as anorange solid. ¹H NMR (300 MHz, CDCl₃): δ=8.22 (s, 1H), 7.49 (d, J=8.8,1H), 7.15 (d, J=8.8, 1H), 5.12 (s, 2H), 3.56 (s, 3H), 3.52 (s, 3H), 3.05(m, 3H), 2.69 (dd, J1=8.1, J2=16.5), 2.54 (m, 1H). MS m/e (M+H)⁺=325.2.

[9-(2,2-Dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Neopentylamine (2.0 mL, 17 mmol) was added to amixture of potassium carbonate (1.2 g, 8.7 mmol) and2-(S)-(4-chloromethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester hydrochloride (1.56 g, 4.3 mmol) in acetonitrile (30 mL). Reactionmixture was heated at reflux until starting material was deemed to beconsumed by HPLC (1.5 hours). Mixture was cooled to room temperaturethen filtered. Filtrate was concentrated in vacuo. Residue was dissolvedin a mixture of toluene (40 mL) and acetic acid (2 mL). Reaction mixturewas heated at reflux until judged complete by HPLC (44 hours). Mixturewas concentrated in vacuo. Residue was dissolved in ethyl acetate (50mL) and washed with saturated aqueous sodium bicarbonate (2×25 mL).Organic was dried (magnesium sulfate), filtered and concentrated invacuo. Silica gel chromatography (ethyl acetate-hexanes) yielded thedesired product in 90% yield as a yellow foam. ¹H NMR (300 MHz, CDCl₃):δ=8.01 (s, 1H), 7.35 (d, J=8.4, 1H), 7.13 (d, J=8.4, 1H), 5.41 (d,J=16.8, 1H), 4.50 (d, J=16.8, 1H), 3.90 (m, 1H), 3.70 (s, 3H), 3.62 (m,1H), 3.50 (d, J=13.9, 1H), 3.18 (d, J=13.5, 1H), 3.05 (m, 2H), 2.43 (dd,J1=16.7, J2=5.3, 1H), 0.83 (s, 9H). MS m/e (M−H)⁻=342.0.

[9-(2,2-Dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Lithium hydroxide monohydrate (335 mg, 8.0 mmol) was added to asolution of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (1.32 g, 3.8 mmol) in methanol (15 mL),tetrahydrofuran (15 mL) and water (15 mL). Reaction mixture was heatedat 50° C. for 1 hour. The organic solvents were removed from the mixturein vacuo. Remaining aqueous was diluted with water (25 mL). Mixture wasneutralized with 1 N hydrochloric acid (8.0 mL). Mixture was extractedwith ethyl acetate (2×30 mL). Combined organic layers were washed withbrine (20 mL) then dried (magnesium sulfate), filtered and concentratedin vacuo. Desired product was obtained in 88% yield as a light yellowsolid. ¹H NMR (300 MHz, CDCl₃): δ=7.98 (s, 1H), 7.36 (d, J=8.8, 1H),7.10 (d, J=8.8, 1H), 5.38 (d, J=16.8, 1H), 4.48 (d, J=16.8, 1H), 3.85(m, 1H), 3.49 (d, J=13.5, 1H), 3.18 (d, J=13.9, 1H), 3.08 (s, 2H), 2.92(dd, J1=8.2, J2=16.3, 1H), 2.55 (dd, J1=16.5, J2=4.8, 1H) 0.81 (s, 9H).MS m/e (M−H)⁻=328.0.

(9-Benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl)-aceticacid methyl ester. Benzylamine (250 μL, 2.3 mmol) and2-(S)-(4-Chloromethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester hydrochloride were converted following a procedure analogous tothe preparation of[9-(2,2-Dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Silica gel chromatography (ethyl acetate-hexanes)afforded the desired product in 62% yield as an amber oil. ¹H NMR (300MHz, CDCl₃): δ=7.77 (s, 1H), 7.28 (m, 6H), 7.09 (d, J=8.4, 1H), 5.18 (d,J=16.8, 1H), 4.99 (d, J=15.0, 1H), 4.43 (d, J=5.9, 1H), 4.39 (d, J=1.8,1H), 4.34 (d, J=4.0, 1H), 3.74 (s, 3H), 3.13 (m, 2H), 2.51 (dd, J1=5.5,J2=16.8, 1H). MS m/e (M+H)⁺=364.0.

(9-Benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl)-aceticacid. Lithium hydroxide (32 mg, 0.76 mmol) and(9-benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl)-aceticacid methyl ester were reacted in a manner analogous to the preparationof[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Desired product was obtained as a yellow oil in 99% yield. ¹H NMR(300 MHz, DMSO, D₆): δ=7.72 (s, 1H), 7.28 (m, 4H), 7.16 (m, 2H), 7.06(d, J=8.8, 1H), 5.15 (d, J=16.8, 1H), 4.95 (d, J=15.0, 1H), 4.37 (m,4H), 3.09 (m, 2H), 2.59 (dd, J1=5.1, J2=16.5, 1H). MS m/e (M+H)⁺=350.0.

[4-Chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Potassium carbonate (190 mg, 1.4 mmol) was added to asolution of2-(S)-(4-acetoxymethyl-7-chloro-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester (240 mg, 0.58 mmol) in methanol (10 mL) and ethanol (5mL). Mixture was stirred at room temperature for 1.5 hours. Reaction wasquenched with the addition of 1 N hydrochloric acid (10 mL). Organicsolvents were removed from the mixture in vacuo. Remaining aqueous wasbasified with sodium bicarbonate. Mixture was extracted 2× ethyl acetate(15 mL). Combined organic layers were dried (magnesium sulfate),filtered and concentrated. Residue was dissolved in dichloromethane (6mL). Thionyl chloride (2 mL) was added to the mixture. Reaction wasstirred at room temperature for 1.5 hours. Mixture was concentrated invacuo. Residue was treated with dichloromethane (25 mL) thenconcentrated in vacuo. Residue was suspended in acetonitrile (5 mL).Potassium carbonate (200 mg, 1.4 mmol) was added to the mixture followedby neopentylamine (150 μL, 1.3 mmol). Reaction mixture was heated atreflux for 1 hour. Mixture was cooled to room temperature then filteredthrough a 0.45 μm PTFE membrane. Filtrate was concentrated. Residue wasdissolved in a mixture of toluene (5 mL) and acetic acid (250 μL).Reaction mixture was heated at 100° C. for 15 hours then warmed toreflux for 7 hours. Mixture was cooled to room temperature then dilutedwith ethyl acetate (15 mL). Mixture was washed successively 2× saturatedaqueous sodium bicarbonate (20 mL), water (15 mL) and brine (10 mL).Organic was dried (magnesium sulfate), filtered and concentrated invacuo. Silica gel chromatography (ethyl acetate-hexanes) afforded thedesired product in 48% yield as a yellow oil. ¹H NMR (300 MHz, CDCl₃):δ=8.02 (s, 1H), 7.13 (s, 1H), 5.37 (m, 1H), 4.42 (d, J=17.2, 1H), 3.88(m, 1H), 3.70 (s, 3H), 3.53 (d, J=13.9, 1H), 3.12 (d, J=13.9, 1H), 3.03(m, 3H), 2.44 (dd, J1=5.9, J2=16.9, 1H), 0.81 (s, 9H). MS m/e(M+H)⁺=378.1.

[4-Chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Lithium hydroxide monohydrate (30 mg, 0.71 mmol) was added to asolution of[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (100 mg, 0.26 mmol) in methanol (2 mL),tetrahydrofuran (2 mL) and water (2 mL). Reaction mixture was stirred atambient temperature for two hours followed by heating at 50° C. for 40minutes. Organic solvents were removed from the mixture in vacuo.Remaining aqueous was neutralized with 1N hydrochloric acid (750 μL).Mixture was extracted 2× ethyl acetate (10 mL). Combined organic layerswere washed with brine (10 mL) then dried (magnesium sulfate), filteredand concentrated in vacuo. Desired product was obtained in 93% yield asan orange solid. ¹H NMR (300 MHz, CDCl₃): δ=7.98 (s, 1H), 7.09 (s, 1H),5.35 (d, J=17.2, 1H), 4.41 (d, J=17.2, 1H), 3.82 (m, 1H), 3.48 (d,J=13.9, 1H), 3.12 (d, J=13.9, 1H), 3.02 (m, 2H), 2.92 (dd, J1=8.4,J2=16.8, 1H), 2.45 (dd, J1=5.1, J2=16.8, 1H), 0.78 (s, 9H), MS m/e(M−H)⁻=362.0.

3-(2-Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester. Palladium (II) acetate (105 mg, 0.43 mmol) was addedto a mixture of acetic acid3-tert-butoxycarbonylamino-6-iodo-2-methyl-benzyl ester (2.89 g, 7.1mmol), Z-dehydroalanine methyl ester (2.20 g, 9.4 mmol),tetrabutylammonium chloride hydrate (2.70 g, 9.7 mmol), and sodiumbicarbonate (1.80 g, 21.4 mmol) in THF (100 mL). Reaction was heated atreflux for 3.75 hours. Mixture was cooled to room temperature thenfiltered through a plug of silica gel eluting 70% ethyl acetate-hexanes(500 mL). Filtrate was concentrated in vacuo. Silica gel chromatographyafforded the title compound as a yellow solid in 69% yield. ¹H NMR (300MHz, CDCl₃): δ=7.79 (d, J=8.4, 1H), 7.42 (s, 1H), 7.27 (m, 6H), 6.30 (s,1H), 5.11 (s, 2H), 5.02 (s, 2H), 3.81 (s, 3H), 2.21 (s, 3H), 2.02 (s,3H), 1.51 (s, 9H). MS m/e (M−H)⁻=511.0.

3-(2-Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester. A solution of3-(2-acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester (2.51 g, 4.9 mmol) in methanol (50 mL) and ethylacetate (15 mL) was reacted in a manner similar to the preparation of2-(S)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester. Title compound was obtained as an off-white solid in97% yield. ¹H NMR (300 MHz, CDCl₃): δ=7.66 (d, J=7.9, 1H), 7.31 (m, 5H),6.99 (d, J=8.5, 1H), 6.21 (s, 1H), 5.31 (d, J=7.6, 1H), 5.17 (d, J=3.7,2H), 5.04 (d, J=5.80, 2H), 4.56 (m, 1H), 3.71 (s, 3H), 3.23 (dd,J1=5.80, J2=14.7, 1H), 3.07 (dd, J1=7.8, J2=14.2, 1H), 2.21 (s, 3H),2.00 (s, 3H), 1.50 (s, 9H). MS m/e (M−H)⁻=513.0.

3-(4-Acetoxymethyl-1H-indazol-5-yl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester. Trifluoroacetic acid (2.5 mL) was added to a solutionof3-(2-acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester (770 mg, 1.5 mmol) in dichloromethane (10 mL).Reaction mixture was stirred at room temperature for 1.5 hours. Mixturewas concentrated in vacuo. Residue was treated with chloroform (40 mL)then concentrated in vacuo. Residue was dissolved in 5% acetic acid inchloroform (10 mL). Isoamyl nitrite (240 μL, 1.8 mmol) was added to themixture. Reaction mixture was stirred at ambient temperature for 20minutes. Potassium acetate (690 mg, 7.0 mmol) was added to the mixture.Reaction mixture was stirred at ambient temperature for 45 minutes.Mixture was washed successively with water (10 mL), and 2× saturatedaqueous sodium bicarbonate (15 mL). Organic was dried (magnesiumsulfate), filtered and concentrated. Crude product was obtained in 81%yield as an amber oil and was used without further purification. ¹H NMR(300 MHz, CDCl₃): δ=8.17 (s, 1H), 7.41 (d, J=8.4, 1H), 7.25 (m, 6H),5.54 (d, J=8.1, 1H), 5.44 (s, 2H), 5.03 (s, 2H), 4.67 (m, 1H), 3.78 (s,3H), 3.37 (dd, J1=5.9, J2=14.3, 1H), 3.22 (dd, J1=8.1, J2=14.3, 1H),1.98 (s, 3H). MS m/e (M+H)⁺=426.0.

2-(R)-Benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionicacid methyl ester hydrochloride. Potassium carbonate (1.65 g, 12 mmol)was added to a solution of3-(4-acetoxymethyl-1H-indazol-5-yl)-2-benzyloxycarbonylamino-propionicacid methyl ester (2.30 g, 5.4 mmol) in methanol (70 mL). Reactionmixture was stirred at room temperature for 2 hours. Reaction wasquenched with 1N hydrochloric acid (50 mL). Methanol was removed fromthe mixture in vacuo. Remaining aqueous was basified with sodiumbicarbonate. Aqueous was extracted with ethyl acetate (2×50 mL).Combined extracts were washed with water (30 mL) and brine (20 mL).Organic was dried (magnesium sulfate), filtered and concentrated.Residue was dissolved in 1:1 ethyl acetate:hexanes (50 mL). 1Nhydrochloric acid in 1,4 dioxane (1.4 mL), was added to the mixturedropwise causing a precipitate to form. Mixture was stirred at roomtemperature for 1 hour. Solids were filtered, washed with 1:1 ethylacetate:hexanes, then dried in vacuo. Product was obtained in 61% yieldas a tan solid. ¹H NMR (300 MHz, DMSO-D₆): δ=8.67 (s, 1H), 7.49 (s, 2H),7.22 (m, 5H), 4.99 (m, 4H), 4.50 (m, 1H), 3.73 (s, 3H), 3.41 (m, 1H),3.13 (dd, J1=9.9, J2=13.9, 1H). MS m/e (M+H)⁺=384.0.

2-(R)-Benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester hydrochloride.2-(R)-Benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionicacid methyl ester hydrochloride was reacted in a manner analogous to thepreparation of 2-(S)-(4-chloromethyl-1H-indazol-5-ylmethyl)-succinicacid dimethyl ester hydrochloride. Title compound was obtained as anorange solid in 99% yield. ¹H NMR (300 MHz, CD₃OD): δ=8.43 (s, 1H), 7.50(d, J=8.8, 1H), 7.38 (d, J=8.4, 1H), 7.24 (m, 5H), 5.06 (d, J=1.0, 1H),4.98 (d, J=4.8, 2H), 4.56 (dd, J1=5.7, J2=9.3, 1H), 3.71 (s, 3H), 3.42(dd, J1=5.5, J2=14.3, 1H), 3.17 (dd, J1=9.3, J2=14.1, 1H). MS m/e(M+H)⁺=402.0.

[9-(2,2-Dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. Neopentylamine (600 μL, 4.5 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester hydrochloride were reacted in a manner analogous tothe preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Silica gel chromatography afforded the title compoundas a lightly colored oil in 88% yield. ¹H NMR (300 MHz, CDCl₃): δ=7.97(d, J=2.9, 1H), 7.38 (d, J=4.0, 3H), 7.31 (m, 3H), 7.06 (dd, J1=3.7,J2=8.8, 6.32 (d, J=6.3, 1H), 5.24 (m, 2H), 5.15 (s, 2H), 4.42 (dd,J1=5.5, J2=17.2, 1H), 3.56 (d, J=13.9, 1H), 3.45 (d, J=16.5, 1H), 3.07(m, 2H), 0.82 (s, 9H). (M+H)⁺=421.0.

7-(R)-Amino-9-(2,2-dimethyl-propyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethanesulfonate. Methanesulfonic acid (1 mL) was added to a solutionof[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (145 mg, 0.34 mmol) and anisole (100 μL, 0.92 mmol) indichloromethane (4 mL). Reaction mixture was stirred at room temperaturefor 2.5 hours. Mixture was diluted with diethyl ether (25 mL). Mixturewas allowed to stand at room temperature for 30 minutes. Solvents weredecanted off. Remaining residue was washed with diethyl ether (25 mL)then dried in vacuo. Crude product was obtained as an orange oil inquantitative yield, and was used without further purification. ¹H NMR(300 MHz, CD₃OD): δ=8.50 (s, 1H), 7.56 (d, J=8.8, 1H), 7.39 (s, J=8.8,1H), 5.42 (d, J=17.9, 1H), 5.10 (dd, J1=4.4, J2=12.4, 1H), 4.75 (d,J=17.6, 1H), 3.84 (d, J=13.5, 1H), 3.42 (m, 3H), 3.10 (d, J=13.9, 1H),2.71 (s, 6H), 0.82 (s, 9H). (M+H)⁺=287.1.

(3-Acetyl-9-benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester. Benzylamine (53 μL, 0.49 mmol) was added to a mixtureof2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (125 mg, 0.31 mmol) and potassium carbonate (50 mg,0.36 mmol) in acetonitrile (5 mL). Reaction was heated at reflux for 1hour. Mixture was cooled to room temperature then filtered. Filtrate wasconcentrated. Residue was dissolved in a mixture of toluene (5 mL) andacetic acid (50 μL). Mixture was heated at reflux for 2 hours. Mixturewas cooled to room temperature. Acetic anhydride (500 μL) was added tothe mixture. Reaction was stirred at room temperature for 2 hours.Mixture was diluted with ethyl acetate (20 mL). Mixture was washedsuccessively with water (15 mL), 1N hydrochloric acid (2×10 mL), andbrine (10 mL). Organic was dried (magnesium sulfate), filtered andconcentrated. Silica gel chromatography (ethyl acetate-hexanes) yieldedthe title compound in 43% yield as an amber oil. ¹H NMR (300 MHz,CDCl₃): δ=8.33 (s, 1H), 7.47 (d, J=8.8, 1H), 7.33 (m, 5H), 7.17 (m, 5H),7.02 (d, J=9.2, 1H), 6.28 (d, J=6.6, 1H), 5.34 (m, 1H), 5.16 (s, 2H),5.00 (m, 1H), 4.84 (m, 1H), 5.43 (t, J=14.5, 1H), 4.43 (d, J=5.9, 1H),4.32 (d, J=16.8, 1h), 4.11 (m, 1H), 2.02 (s, 3H). MS m/e (M+H)⁺=483.2.

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(3-acetyl-9-benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-amide.A catalytic amount of 10% palladium on carbon was added to a mixture ofacetic acid (200 μL) and(3-acetyl-9-benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester (65 mg, 0.13 mmol) in methanol (10 mL). Reactionvessel was charged with 50 psi of hydrogen gas and placed on a Parrhydrogenation apparatus. Reaction mixture was shaken at room temperaturefor 2 hours. Mixture was filtered. Filtrate was concentrated. Residuewas partitioned between dichloromethane (10 mL) and saturated aqueoussodium bicarbonate (5 mL). 20% phosgene in toluene (170 μL, 0.32 mmol)was added to the mixture with vigorous stirring.4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidinium acetate (110 mg,0.38 mmol) was added to the mixture. Reaction mixture was stirredvigorously for 45 minutes. Layers were separated. Organic was washedwith brine (10 mL) then dried (magnesium sulfate) and concentrated invacuo. Preparatory reverse phase HPLC (acetonitrile—water, 0.2%trifluoroacetic acid) followed by removal of the acetonitrile in vacuoyielded an aqueous solution containing the title compound. Extractedfrom the aqueous solution with dichloromethane (20 mL). Combinedextracts were washed with brine (20 mL). Organic was dried (magnesiumsulfate), filtered and concentrated. Desired product was obtained as awhite solid in 23% yield. MS m/e (M+H)⁺=606.4. rf=2.09 min.

(3-Acetyl-9-methyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester. Methylamine solution in methanol (2M, 2 mL, 4 mmol)was added to a mixture of potassium carbonate (130 mg, 0.94 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (165 mg, 0.41 mmol) in acetonitrile (5 mL). Mixturewas heated at 40° C. for 1 hour. Mixture was cooled to room temperature.Mixture was filtered. Filtrate was concentrated. Residue was treatedwith a mixture of toluene (5 mL) and acetic acid (200 μL). Mixture washeated at reflux for 45 minutes. Mixture was cooled to room temperaturethen acetic anhydride was added (2 mL). Reaction was stirred at roomtemperature for 16 hours. Mixture was diluted with ethyl acetate (10 mL)then washed successively with water (10 mL), saturated aqueous sodiumbicarbonate (2×15 mL) and brine (10 mL). Organic was dried (magnesiumsulfate), filtered and concentrated. Silica gel chromatography (ethylacetate-hexanes) yielded the desired product as a yellow solid in 18%yield. ¹H NMR (300 MHz, CDCl₃): δ=8.70 (s, 1H), 7.51 (d, J=9.2, 1H),7.34 (m, 5H), 7.05 (d, J=9.2, 1 H), 6.19 (m, 1H), 5.23 (s, 2H), 5.13 (s,2H), 4.18 (d, J=17.2, 1H), 3.46 (d, J=17.2, 1H), 3.11 (s, 3H), 2.95 (m,1H), 2.89 (s, 3H). MS m/e (M+H)⁺=407.2.

[8-Oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. 1-(2-Aminoethyl)piperidine (150 μL, 1.1 mmol) wasadded to a mixture of potassium carbonate (150 mg, 1.1 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester hydrochloride (220 mg, 0.50 mmol) in acetonitrile (5mL). Reaction was heated at reflux for 1 hour. Mixture was cooled toroom temperature then concentrated. Residue was dissolved in a mixtureof dichloromethane (10 mL) and acetic acid (200 μL). Mixture was heatedat 40° C. for 32 hours and heated at reflux for 8 hours. Mixture wascooled to room temperature then washed successively with saturatedaqueous sodium bicarbonate (2×10 mL), water (10 mL) and brine (10 mL).Organic was dried (magnesium sulfate), filtered and concentrated. Crudeproduct was obtained as a maroon solid in 86% yield. Material wascarried forward without further purification. MS m/e (M+H)⁺=462.4. HPLCrf=1.19 min.

7-(R)-Amino-9-(2-piperidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Methanesulfonic acid (1 mL) was added to a mixture of anisole (100 μL,0.92 mmol) and[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (200 mg, 0.43 mmol) in dichloromethane (4 mL).Reaction was stirred at ambient temperature for 1 hour. Mixture wasdiluted with diethyl ether (30 mL). Mixture was allowed to stand at roomtemperature for 15 minutes. Solvents were decanted off. Remainingresidue was dissolved in water (5 mL). Mixture was washed with diethylether (2×10 mL). Aqueous was basified with 1N sodium hydroxide (2 mL).Mixture was extracted with ethyl acetate (2×15 mL). Combined extractswere washed with brine (5 mL). Organic was dried (magnesium sulfate),filtered and concentrated. Title compound was obtained as an amber oilin 42% yield. Material was carried forward without further purification.¹H NMR (300 MHz, CDCl₃): δ=8.06 (S, 1H), 7.35 (d, J=8.4, 1H), 7.11 (d,J=8.4, 1H), 5.16 (d, J=16.8, 1H), 4.57 (d, J=16.8, 1H), 4.40 (dd,J1=12.8, J2=4.4, 1H), 3.77 (m, 1H), 3.54 (m, 1H), 3.29 (m, 1H), 3.03 (m,1H), 2.36 (m, 6H), 2.14 (m, 2H), 1.38 (m, 4H). MS m/e (M+H)⁺=328.3.

[8-Oxo-9-(2-pyrrolidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. 1-(2-Aminoethyl)pyrrolidine (90 μL, 0.71 mmol) wasadded to a mixture of2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (100 mg, 0.23 mmol) and potassium carbonate (120 mg,0.87 mmol) in acetonitrile (5 mL). Reaction was heated at reflux untilHPLC suggested the starting material had been consumed (2 hours).Mixture was cooled to room temperature then filtered. Acetic acid (200μL) was added to the filtrate. Reaction was heated at reflux untiljudged complete by HPLC (1 hour). Mixture was diluted with ethyl acetate(20 mL) then washed successively with saturated aqueous sodiumbicarbonate (15 mL), water (10 mL) and brine (10 mL). Organic was dried(magnesium sulfate), filtered and concentrated. Crude product wasobtained in 69% yield as a yellow oil. Material was carried forwardwithout further purification. ¹H NMR (300 MHz, CDCl₃): δ=8.04 (s, 1),7.38 (m, 5H), 7.28 (d, J=8.4, 1H), 7.02 (d, J=8.8, 1H), 6.25 (d, J=6.2,1H), 5.25 (m, 1H), 5.15 (s, 2H), 4.56 (d, J=16.8, 1H), 3.70 (m, 2H),3.47 (dd, J1=3.5, J2=16.7, 1H), 3.01 (m, 1H), 2.62 (m, 2H), 2.48 (m,3H), 1.74 (m, 4H). MS m/e (M+H)⁺=448.4.

7-(R)-Amino-9-(2-pyrrolidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained from[8-oxo-9-(2-pyrrolidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester following a procedure analogous to the preparation of7-(R)-amino-9-(2-piperidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as an amber oil in 52% yield and used withoutfurther purification. ¹H NMR (300 MHz, DMSO-D₆): δ=8.06 (s, 1H), 7.33(d, J=8.8, 1H), 7.10 (d, J=8.8, 1H), 5.16 (d, J=16.8, 1H), 5.48 (d,J=16.8, 1H), 4.40 (dd, J1=13.0, J2=4.2, 1H), 3.67 (m, 2H), 3.29 (dd,J1=3.11, J2=17.0 1H), 3.01 (dd, J1=16.8, J2=12.8, 1H), 2.58 (m, 2H)m1.87 (m, 4H), 1.67 (m 4H). MS m/e (M+H)⁺=422.4.

[9-(2-Dimethylamino-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. N,N-Ethylenediamine (70 μL, 0.66 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (100 mg, 0.23 mmol) were converted to the titlecompound following a procedure analogous to the preparation of[8-oxo-9-(2-pyrrolidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. Crude product was obtained as an amber oil in 52%yield. Material was carried forward without further purification. ¹H NMR(300 MHz, CDCl₃): δ=7.99 (s, 1H), 7.36 (m, 6H), 6.27 (d, J=6.2, 1H),5.25 (m, 1H), 5.16 (s, 2H), 5.13 (m, 1H), 5.06 (d, J=18.7, 1H), 4.52 (d,J=17.2, 1H), 3.61 (t, J=6.8, 2H), 3.45 (dd, J1=2.4, J2=16.7, 1H), 3.01(m, 1H), 2.38 (m, 2H), 2.11 (s, 6H), MS m/e (M+H)⁺=422.4.

7-(R)-Amino-9-(2-dimethylamino-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.[9-(2-Dimethylamino-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (65 mg, 0.15 mmol) was converted to the desiredproduct in a manner analogous to the preparation of7-(R)-amino-9-(2-pyrrolidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Crude material was obtained as a yellow oil in 25% yield. Material wascarried forward without further purification. ¹H NMR (300 MHz, CDCl₃):δ=8.07 (s, 1H), 7.35 (d, J=8.4, 1H), 7.12 (d, J=8.4, 1H), 5.15 (d,J=16.8, 1H), 4.58 (d, J=16.8, 1H), 4.42 (dd, J1=4.8, J2=12.8, 1H), 3.62(m, 2H), 3.30 (m, 1H), 3.01 (dd, J1=13.0, J2=16.7, 1H), 2.37 (m, 2H),2.15 (s, 6H). MS m/e (M+H)⁺=288.3.

[9-(2-Morpholin-4-yl-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. 4-(2-Aminoethyl)morpholine (90 μL, 0.69 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (100 mg, 0.23 mmol) were converted into the titlecompound following a procedure analogous to the preparation of[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. Crude material was obtained as an amber oil in 92%yield. Product was carried forward without further purification. MS m/e(M+H)⁺=464.4. HPLC rf=1.15 min.

7-(R)-Amino-9-(2-morpholin-4-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.[9-(2-Morpholin-4-yl-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (95 mg, 0.20 mmol) was converted into the titlecompound following a procedure analogous to the preparation of7-(R)-amino-9-(2-piperidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Crude product was obtained as an amber oil in 62% yield. Material wascarried forward without further purification. ¹H NMR (300 MHz, CDCl₃):δ=8.06 (s, 1H), 7.34 (d, J=8.4, 1H), 7.15 (d, J=8.8, 1H), 5.22 (d,J=16.8, 1H), 4.51 (d, J=17.2, 2H), 4.44 (m, 1H), 4.02 (m, 1H), 3.40 (t,J=4.8, 4H), 3.31 (m, 3H), 3.07 (m, 1H), 2.32 (m, 4H), 1.95 (m, 2H). MSm/e (M+H)⁺=330.3.

[8-Oxo-9-(1-(S)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. (S)-(−)-α-Methylbenzylamine (85 μL, 0.67 mmol)and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (100 mg, 0.23 mmol) were converted into the desiredproduct following a procedure analogous to the preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Crude product was obtained as a dark oil inquantitative yield. Material was carried forward without furtherpurification. MS m/e (M+H)⁺=455.3. HPLC rf=1.68 min.

7-Amino-9-(1-(S)-phenyl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-8-one.[8-Oxo-9-(1-(S)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (105 mg, 0.23 mmol) was reacted in a manner analogousto the preparation of7-(R)-amino-9-(2-piperidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Crude product was obtained as a dark oil in 82% yield. Material wascarried forward without further purification. MS m/e (M−H)⁻=319.3. HPLCrf=1.49 min.

[8-Oxo-9-(1-(R)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. (R)-(+)-α-Methylbenzylamine (85 μL, 0.67 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (100 mg, 0.23 mmol) were converted into the titlecompound in a manner similar to the preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Crude material was obtained as a dark foam inquantitative yield. Material was carried forward without furtherpurification. MS m/e (M−H)⁻=453.4. HPLC rf=1.98 min.

7-Amino-9-(1-(R)-phenyl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-8-one.[8-Oxo-9-(1-(R)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (105 mg, 0.23 mmol) was reacted in a manner analogousto the preparation of7-(R)-amino-9-(2-piperidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Crude product was obtained as a maroon solid in 78% yield. Material wascarried forward without further purification. ¹H NMR (300 MHz, CDCl₃):δ=7.88 (s, 1H), 7.40 (m, 6H), 7.14 (d, J=8.8, 1H), 6.85 (m, 1H), 6.09(m, 1H), 4.67 (d, J=16.8, 1H), 4.47 (dd, J1=4.6, J2=12.6, 1H), 4.25 (d,J=17.2, 1H), 1.48 (d, J=7.0, 3H). MS m/e (M−H)⁻=319.3.

[8-Oxo-9-(4-trifluoromethyl-benzyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. 4-Trifluoromethylbenzylamine (72 μL, 0.51 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (100 mg, 0.23 mmol) were converted into the titlecompound in a manner similar to the preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Crude material was obtained as a dark brown solid inquantitative yield. Material was carried forward without furtherpurification. MS m/e (M+H)⁺=509.4. HPLC rf=1.67 min.

7-Amino-9-(4-trifluoromethyl-benzyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-8-onebis-methanesulfonate.[8-Oxo-9-(4-trifluoromethyl-benzyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester was converted into the title compound in a manneranalogous to the preparation of7-(R)-amino-9-(2,2-dimethyl-propyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethaneslufonate. Crude material was obtained as a dark foam inquantitative yield. Material was carried forward without furtherpurification. MS m/e (M+H)⁺=375.2. HPLC rf=1.00 min.

(9-Isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester. Isopropylamine (300 μL, 3.5 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester were converted into the title compound following aprocedure analogous to the preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Crude product was obtained as a dark oil inquantitative yield. Material was carried forward without furtherpurification. ¹H NMR (500 MHz, CDCl₃): δ=8.09 (s, 1H), 7.39 (m, 3H),7.23 (m, 2H), 7.17 (m, 1H), 6.32 (d, J=5.8, 1H), 5.25 (m, 1H), 5.15 (m,2H), 4.90 (m, 1H), 4.82 (d, J=17.4, 1H), 4.51 (m, 1H), 3.51 (m, 1H),3.05 (t, J=13.6, 1H), 1.56 (s, 6H). MS m/e (M+H)⁺=393.4.

7-(R)-Amino-9-isopropyl-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethanesulfonate.(9-Isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester (90 mg, 0.23 mmol) was converted into the titlecomound following a procedure analogous to the synthesis of7-(R)-amino-9-(2,2-dimethyl-propyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethaneslufonate. Crude product was obtained as a dark oil inquantitative yield. Crude material was carried forward without furtherpurification. MS m/e (M+H)⁺=259.2. HPLC rf=0.60 min.

[9-(3,3-Dimethyl-butyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. 3,3-Dimethylbutylamine (100 μL, 0.74 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester were converted into the title compound following aprocedure analogous to the preparation of[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. Crude material was obtained as a dark oil inquantitative yield. Material was carried forward without furtherpurification. ¹H NMR (300 MHz, CDCl₃): δ=8.03 (m, 1H), 4.38 (m, 4H),7.31 (m, 2H), 7.06 (d, J=8.4, 1H), 6.26 (d, J=6.2, 1H), 5.23 (m, 1H),5.14 (s, 2H), 5.08 (m, 1H), 4.35 (dd, J1=8.8, J2=17.2, 1H), 3.50 (m,2H), 1.33 (dd, J1=6.2, J2=11.0, 2H), 0.91 (m, 2H), 0.85 (s, 9H). MS m/e(M+H)⁺=435.1.

7-(R)-Amino-9-(3,3-dimethyl-butyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethanesulfonate.[9-(3,3-Dimethyl-butyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (100 mg, 0.23 mmol) was converted into the titlecompound following a procedure analogous to the preparation of7-(R)-amino-9-(2,2-dimethyl-propyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethaneslufonate. Crude material was obtained as a dark oil inquantitative yield. Material was carried forward without furtherpurification. MS m/e (M+H)⁺=301.2. HPLC rf=1.11 min.

4-(7-(R)-Benzyloxycarbonylamino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylicacid tert-butyl ester. 4-Amino-1-N-Boc-piperidine (110 mg, 0.55 mmol)and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (150 mg, 0.34 mmol) was converted into the titlecompound in a manner analogous to the preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Crude product was obtained as a dark foam inquantitative yield. Material was carried forward without furtherpurification. ¹H NMR (300 MHz, CDCl₃): δ=8.05 (m, 1H), 7.35 (m, 6H),7.15 (m, 1H), 6.27 (m, 1H), 5.28 (m, 1H), 5.15 (s, 2H), 4.87 (d, J=16.5,1H), 4.63 (m, 1H), 4.47 (m, 1H), 4,24 (m, 1H), 3.99 (m, 1H), 3.49 (m,1H), 3.04 (m, 1H), 2.83 (m, 2H), 2.63 (m, 1H), 1.90 (m, 1H), 1.74 (m,2H), 1.58 (s, 9H). MS m/e (M−H)⁻=532.1.

4-(7-(R)-Amino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylicacid tert-butyl ester acetate. A catalytic amount of 10% palladium oncarbon was added to a solution of4-(7-(R)-Benzyloxycarbonylamino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylicacid tert-butyl ester (200 mg, 0.37 mmol) and acetic acid (100 μL, 1.7mmol) in methanol (10 mL). Reaction vessel was placed on a Parrapparatus and charged with 30 psi of hydrogen gas. Mixture was allowedto shake at room temperature for 3 hours. Mixture was filtered. Filtratewas concentrated in vacuo. Crude compound was obtained as a dark oil inquantitative yield. Material was carried forward without furtherpurification. ¹H NMR (300 MHz, CDCl₃): δ=8.06 (s, 1H), 7.36 (d, J=8.8,1H), 7.12 (d, J=8.8, 1H), 4.92 (d, J=17.6, 1 H), 4.67 (m, 1H), 4.49 (d,J=17.2, 1H), 4.26 (m, 1H), 3.98 (m, 2H), 3.05 (m, 1H), 2.83 (m, 2H),2.64 (m, 1H), 1.89 (m, 1H), 1.73 (m, 1H), 1.45 (d, J=2.9, 9H), 1.25 (m,2H).MS m/e (M−C₄H₈+H)⁺=344.2.

3-(2-Acetoxymethyl-4-amino-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester.3-(2-Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester was converted into3-(2-Acetoxymethyl-4-amino-3-methyl-phenyl)-2-benzyloxycarbonylamino-(R)-propionicacid methyl ester following an analogous procedure to the synthesis of2-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-(S)-succinic acid diethylester. Desired product was obtained as an yellow oil in 95% yield. ¹HNMR (300 MHz, CDCl₃): δ=7.31 (m, 5H); 6.81 (d, J=8.1, 1H); 6.65 (d,J=8.4, 1H); 5.35 (d, J=8.1, 1H); 5.15 (s, 2H); 5.04 (s, 2H); 4.53 (m,1H); 3.71 (s, 3H); 3.16 (m, 1H); 3.01 (m, 1H); 2.12 (s, 3H); 1.99 (s,3H). MS m/e (M+H)⁺=415.2.

3-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester. Desired product was obtained from3-(2-Acetoxymethyl-4-amino-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester in a manner analogous to the preparation of2-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-(S)-succinic aciddiethyl ester. Silica gel chromatography (ethyl acetate-hexanes)afforded the product as an yellow oil in 40% yield. ¹H NMR (300 MHz,CDCl₃): δ=7.31 (m, 5H); 6.96 (s, 1H); 5.36 (d, J=8.4, 1H); 5.12 (s, 2H);5.05 (s, 2H), 4.53 (m, 1H); 3.72 (s, 3H); 3.15 (m, 1H), 2.99 (m, 1H);2.15 (s, 3H); 1.99 (s, 3H). MS m/e (M−C₂H₄O₂+H)⁺=398.3.

3-(4-Acetoxymethyl-7-chloro-1H-indazol-5-yl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester. Trifluoroacetic acid (70 μL, 0.91 mmol) was added toa solution of3-(2-acetoxymethyl-4-amino-5-chloro-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester (345 mg, 0.77 mmol) in 5% acetic acid in chloroform(5.2 mL). Isoamyl nitrite (120 μL, 0.89 mmol) was added to the mixturedrop-wise. Reaction mixture was stirred at room temperature for 40minutes. Potassium acetate (300 mg, 3.1 mmol) was added to the mixture.Reaction mixture was stirred at room temperature for 45 minutes. Mixturewas diluted with dichloromethane (10 mL) then washed successively withwater (2×10 mL), and saturated aqueous sodium bicarbonate (2×10 mL).Organic was dried (magnesium sulfate), filtered and concentrated invacuo. Crude product was obtained as an orange solid in 83% yield.Material was carried forward without further purification. ¹H NMR (300MHz, CDCl₃): δ=8.20 (s, 1H); 7.29 (m, 5H); 7.21 (s, 1H); 5.53 (d, J=7.7,1H); 5.40 (s, 2H); 5.04 (s, 2H); 4.67 (m, 1H); 3.74 (s, 3.74 (s, 3H);3.34 (m, 1H); 3.21 (m, 1H); 2.02 (s, 3H). MS m/e (M+H)⁺=460.1.

2-(R)-Benzyloxycarbonylamino-3-(7-chloro-4-hydroxymethyl-1H-indazol-5-yl)-propionicacid methyl ester.3-(4-Acetoxymethyl-7-chloro-1H-indazol-5-yl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester (290 mg, 0.63 mmol) was converted into the desiredproduct in a manner analogous to the preparation of2-(R)-benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionicacid methyl ester. Crude product was obtained as an orange solid in 95%yield. Material was carried forward without firther purification. ¹H NMR(300 MHz, CDCl₃): δ=8.15 (s, 1H); 7.27 (m, 5H); 7.14 (s, 1H); 6.10 (m,1H); 5.01 (d, J=4.8, 2H); 4.95 (s, 2H); 4.75 (m, 1H); 3.79 (s, 3H); 3.34(m, 1H); 3.09 (m, 1H). MS m/e (M+H)⁺=418.0.

2-(R)-Benzyloxycarbonylamino-3-(7-chloro-4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester. Thionyl chloride (2 mL) was added to a solution of2-(R)-benzyloxycarbonylamino-3-(7-chloro-4-hydroxymethyl-1H-indazol-5-yl)-propionicacid methyl ester (245 mg, 0.59 mmol) in dichloromethane (3 mL). Mixturewas stirred at room temperature for 1.5 hours. Mixture was concentrated.Residue was dissolved in dichloromethane (15 mL) then washed withsaturated aqueous sodium bicarbonate (2×10 mL). Organic was dried(magnesium sulfate), filtered and concentrated. Title compound wasobtained as an orange solid in 86% yield. Material was carried forwardwithout further purification. ¹H NMR (300 MHz, CDCl₃): δ=8.19 (s, 1H),7.32 (m, 5H), 7.16 (s, 1H), 5.49 (d, J=7.3, 2H), 5.07 (d, J=4.4, 2H),4.85 (s, 2H), 4.68 (d, J=7.0, 1H), 3.72 (s, 3H), 3.27 (m, 2H). MS m/e(M+H)⁺=436.1.

[4-Chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. Neopentylamine (200 μL, 1.7 mmol) was added to amixture of2-(R)-benzyloxycarbonylamino-3-(7-chloro-4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (180 mg, 0.41 mmol) and potassium carbonate (160 mg,1.2 mmol) in acetonitrile (5 mL). Reaction was heated at reflux for 1hour. Mixture was cooled to room temperature then filtered through a0.45 μm PTFE syringeless filter system. Filtrate was concentrated.Residue was dissolved in a mixture of toluene (5 mL) and acetic acid(200 μL). Mixture was heated at 110° C. overnight. Mixture was dilutedwith ethyl acetate (15 mL) then washed successively with water (15 mL),saturated aqueous sodium bicarbonate (2×15 mL) and brine (10 mL).Organic was dried (magnesium sulfate), filtered and concentrated. Silicagel chromatography afforded the title compound in 52% yield as a yellowsolid. ¹H NMR (300 MHz, CDCl₃): δ=7.89 (d, J=10.6, 1H), 7.38 (m, 5H),6.96 (d, J=10.3, 1H), 6.35 (d, J=5.9, 1H), 5.25 (m, 1H), 5.19 m, 2H),4.28 (m, 1H), 3.66 (m, 1H), 3.40 (m, 1H), 2.96 (dd, J1=13.9, J2=5.5,2H), 0.45 (d, J=2.6, 9H). MS m/e (M+H)⁺=455.2.

(9-Benzyl-4-chloro-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester. Title compound was obtained from benzylamine (100 μL,0.92 mmol) and2-(R)-Benzyloxycarbonylamino-3-(7-chloro-4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (210 mg, 0.48 mmol) following a procedure analogous tothe preparation of[4-Chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. Silica gel chromatography (ethyl acetate-hexanes)afforded the desired product as a yellow solid in 52% yield. ¹H NMR (300MHz, CDCl₃): δ=7.64 (s, 1H), 7.38 (m, 5H), 7.19 (m, 3H), 7.12 (m, 2H),7.00 (s, 1H), 6.36 (d, J=6.2 1H), 5.28 (m, 1H), 5.21 (s, 2H), 5.19 (m,1H), 4.88 (m, 1H), 4.75 (d, J=16.8, 1H), 4.34 (d, J=14.6, 1H), 3.49 (m,1H), 3.03 (m, 1H). MS m/e (M+H)⁺=475.0.

Acetic acid 3-acetylamino-6-iodo-2,4-dimethyl-benzyl ester. To a wellstirred solution of (3-amino-2,4-dimethyl-phenyl)-methanol (1.5 g) inmethanol (70 mL) and solid sodium hydrogen carbonate (4.0 eq) was addeda 1.0 M solution of iodine monochloride dropwise over a period of 5 minat 0° C. The cooling bath was removed after the addition of iodinemonochloride. The reaction mixture was brought to room temperature andstirring continued for another 1 h. The reaction mixture wasconcentrated to remove most of methanol, diluted with dichloromethane(50 mL) and washed with 10% solution of sodium thiosulfate and dried(Na2SO4). The desired compound was purified by trituration withdichloromethane and hexane to give in 1.9 g of iodide. The iodide wasthen treated with dichloromethane (100 mL) followed by acetic anhydride(4 eq) and catalytic amount of dimethylaminopyridine and stirred for aperiod of 12 h at room temperature. The reaction mixture was then washedwith aqueous sodium hydrogen carbonate, 1.0 M hydrochloric acid anddried (Na2SO4). The desired compound was triturated with dichloromethaneand hexane to give acetic acid 3-acetylamino-6-iodo-2,4-dimethyl-benzylester in 95% yield. ¹H NMR (300 MHz, CDCl₃): in δ 7.68 (s, 1 H), 6.68(s, 1 H), 2.28 (s, 3 H), 2.25 (s, 3 H), 2.18 (s, 3 H), 2.07(s, 3 H); MS(ESI) 384 (M+Na); R_(f)=1.12.

Acetic acid 5-benzyloxy-2-iodo-benzyl ester. To a well stirred solutionof 3-benzyloxybenzyl alcohol (5.5 g, 25.7 mmol) in methanol (100 mL) andsodium hydrogencarbonate (8.4 g, 100 mmol) was added a 1.0 M solution ofiodine monochloride in dichloromathane (30 mL) at 0° C. The reactionmixture was brought to room temperature and stirring continued foradditional 1 h. The reaction mixture was concentrated and then dilutedwith dicholomethane (150 mL), washed with 10% aqueous sodium thiosulfateand dried (Na₂SO₄). The desired compound was purified by flashchromatography (silica) using 20% ethyl acetate in hexane to give5-benzyloxy-2-iodobenzyl alcohol (6.2 g, 71% yield). The alcohol (4.2 g,12.4 mmol) was dissolved in dichloromethane (100 mL) added aceticanhydride (2.52 g, 24.7 mmol) and catalytic amount of4-dimethylaminopyridine. The reaction mixture was then stirred for 12 h,washed with aqueous sodium hydrogencarbonate and then dried (Na₂SO₄) togive acetic acid 5-benzyloxy-2-iodo-benzyl ester in quantitative yield.MS (ESI) 405 (M+Na) ; R_(f)=2.27.

3-(2-Acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-acrylicacid methyl ester. In a manner similar to2-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzylidene)-succinicacid diethyl ester,3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-acrylicacid methyl ester was prepared by reacting acetic acid5-benzyloxy-2-iodo-benzyl ester with 2-tert-butoxycarbonylamino-acrylicacid methyl ester in 74% yield. MS (ESI) 456 (M+H); R_(f)=1.87.

3-(2-Acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester. To a solution of3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-acrylicacid methyl ester (1.9 g, 4.2 mmol) in anhydrous methanol under nitrogenatmosphere was added1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclootadiene)rhodium (I)trifluoromethanesulfonate (50 mg) and stirred on a Parr shaker at 50 psiof hydrogen atmosphere for 18 h. The solvent was evaporated and thedesired product was crystallized from ethyl acetate-hexane in 90% yield.MS (ESI) 458 (M+H); R_(f)=1.81.

(8-Benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamicacid tert-butyl ester. To a solution of3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester (1.85 g, 4.0 mmol) in methanol (40 mL) was addedpotassium carbonate (560 mg, 4.0 mmol) at room temperature and stirredfor 1 h. The reaction mixture was diluted with dichloromethane (150 mL),washed with 1.0 M aqueous hydrogen chloride and dried (Na₂SO₄) to givethe pure3-(4-benzyloxy-2-hydroxymethyl-phenyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester in almost quantitative yield. To the alcohol (800 mg,1.93 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride(0.18 mL, 2.3 mmol) followed by triethylamine (0.38 mL, 2.70 mmol) at 0°C. and then brought to room temperature. After 1 h, the reaction mixturewas washed with aqueous sodium hydrogencarbonate, dried (Na₂SO₄). Thesolvent was removed, dissolved the crude product in anhydrous THF (20mL) followed by addition of 2.0 M solution of methylamine in THF (10 mL)in a sealed tube. The sealed tube was heated at 80° C. for a period of12 h and then removed the solvent. The crude product was purified byflash chromatography using 30% ethyl acetate in hexane to give(8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamicacid tert-butyl ester in 39% overall yield. ¹H NMR (500 MHz, CDCl₃): inδ 7.40-7.31 (m, 5 H), 7.01-7.00 (m, 1 H), 6.83-6.82 (m, 1 H), 6.66 (s, 1H), 5.91-5.90 (m, 1 H), 5.13-5.01 (m, 4 H), 3.50-3.46 (m, 1 H), 3.03 (s,3 H), 2.85-2.78 (m, 1 H), 1.45 (s, 9 H).

Acetic acid 3-tert-butoxycarbonylamino-6-iodo-2-methyl-benzyl ester. Toa well stirred solution of 3-amino-2-methylbenzyl alcohol (10 g, 72.9mmol) in methanol (250 mL) was added a 1.0 M solution of iodinemonochloride in dichloromethame (76.6 mL) dropwise over a period of 5min at 0° C. The reaction mixture was then brought to room temperatureand stirring continued for additional 2 h. The reaction mixture was thenconcentrated, diluted with dichloromethane (250 mL), washed with 10%aqueous sodium thiosulphate and dried (Na2SO4). The solvent wasevaporated and the crude product was dissolved in THF (200 mL).Di-tert-butyl dicarbonate (15.9 g, 72.9 mmol) was added and the reactionmixture was refluxed for 48 h. The reaction mixture was then dilutedwith ether (400 mL) washed with 1 M HCl (2×10 mL) followed by brine anddried (Na2SO4). The solvent was removed and the desired product wascrystallized from 20% ethyl acetate in hexane to give(3-hydroxymethyl-4-iodo-2-methyl-phenyl)-carbamic acid tert-butyl ester(12.5 g). The filtrate was then concentrated and the desired product waspurified by flash chromatography (silica) using 30% ethyl acetate togive additional 2.5 g of(3-hydroxymethyl-4-iodo-2-methyl-phenyl)-carbamic acid tert-butyl ester.To a stirred solution of3-hydroxymethyl-4-iodo-2-methyl-phenyl)-carbamic acid tert-butyl ester(14.5 g, 40 mmol) in dichloromethane (150 mL) was added acetic anhydride(7.5 mL, 80 mmol) and catalytic amount of 4-dimethylaminopyridine andstirred for 12 h at room temperature. The reaction mixture was thenquenched with aqueous sodium hydrogencarbonate, brine and dried(Na₂SO₄). The solvent was removed and the crude product was purified bycrystallization from dichloromethane and hexane to give acetic acid3-tert-butoxycarbonylamino-6-iodo-2-methyl-benzyl ester (15.5 g, 94%).¹H NMR (500 MHz, CDCl₃): in δ 7.71 (d, J=8.5 Hz, 1 H), 7.25 (d, J=8.5Hz, 1 H), 5.30 (s, 2 H), 2.28 (s, 3 H), 2.08 (s, 3 H), 1.50 (s, 9 H); MS(ESI) 428 (M+Na); R_(f)=1.59.

3-(2-Acetoxymethyl-4-acetylamino-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester. In a manner similar to2-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzylidene)-succinicacid diethyl ester,3-(2-acetoxymethyl-4-acetylamino-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester was prepared by reacting acetic acid3-acetylamino-6-iodo-2,4-dimethyl-benzyl ester with2-benzyloxycarbonylamino-acrylic acid methyl ester in 74% yield. MS(ESI) 491 (M+H); R_(f)=1.87.

3-(2-Acetoxymethyl-4-acetylamino-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-propionicacid methyl ester. In a manner similar to3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-acrylicacid methyl ester,3-(2-acetoxymethyl-4-acetylamino-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-propionicacid methyl ester was prepared from3-(2-acetoxymethyl-4-acetylamino-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester (1.5 g) using1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclootadiene)rhodium (I)trifluoromethanesulfonate (25 mg) in 98% yield. MS (ESI) 491 (M+H);R_(f)=1.87.

(8-Acetylamino-2,7,9-trimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamicacid benzyl ester. In a manner similar to2-(R)-benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionicacid methyl ester hydrochloride, the title compound was prepared byhydrolyzing3-(2-acetoxymethyl-4-acetylamino-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-propionicacid methyl ester (1.84 g, 3.78 mmol) with potassium carbonate (525 mg,3.8 mmol) in MeOH (40 mL). The alcohol was dissolved in dichloromethane(100 mL) and then treated with methanesulfonyl chloride (0.35 mL, 4.5mmol) and triethylamine (0.68 mL, 4.9 mmol). The reaction mixture wasstirred for 12 h, washed with aqueous sodium hydrogencarbonate, 1.0 Maqueous hydrogen chloride and dried (Na₂SO₄). The solvent was removed togive pure3-(4-acetylamino-2-chloromethyl-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-propionicacid methyl ester in almost quantitative yield. The chloride (480 mg,1.08 mmol) was treated with 1.0 M methylamine solution in THF in asealed tube for 3 h at 90° C. The solvent was removed and the crudeproduct was dissolved in toluene and acetic acid (0.5 mL) and refluxedfor 2 h to give(8-acetylamino-2,7,9-trimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamicacid benzyl ester in 68% yield. To the acetate in chloroform (20 mL) wasadded acetic acid (0.5 mL) followed by isoamylnitrite (1.0 mL) and18-crown-6 (50 mg). The reaction mixture was refluxed for 12 h andremoved the solvent. The crude product was purified by flashchromatography using ethyl acetate as eluent to give(4,9-dimethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester as a major product in 37% overall yield. ¹H NMR (500MHz, CDCl₃): in δ 7.96 (s, 1 H), 7.35-7.24 (m, 5 H), 6.7 (s, 1 H),6.43-6.41 (m, 1 H), 5.25-5.05 (m, 3 H), 4.18-4.10 (m, 2 H), 3.07-3.05(m, 2 H), 3.00)s, 3 H), 2.40 (s, 3 H).

(9-Isobutyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester. In a manner similar to[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester, the title compound was prepared by treating2-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester, hydrochloride with isobutylamine followed bytreatment with acetic acid in refluxing toluene to give(9-Isobutyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester in 91% yield. MS (ESI) 407 (M+H) ; R_(f)=1.58.

(8-Oxo-9-pyridin-4-ylmethyl-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester. In a manner similar to[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester, the title compound was prepared by treating2-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester, hydrochloride with 4-(aminomethyl)pyridine followedby treatment with acetic acid in refluxing toluene to give(8-oxo-9-pyridin-4-ylmethyl-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester in 65% yield. MS (ESI) 442 (M+H) ; R_(f)=1.10.

4-Iodo-2-methyl-3-nitrobenzenamine. To a well stirred solution of2-methyl-3-nitroaniline (10 g, 66 mmol) in methanol (150 mL) was addedsodium hydrogencarbonate (264 mmol) followed by 1.0 M solution of iodinemonochloride (72 mmol) at room temperature. After stirring for 1 h, thesolvent was removed, diluted with ether, washed with 10% aqueous sodiumthiosulfate solution. The solvent was removed and the crude iodide wasin the next step.

(E)-Diethyl 2-(4-amino-3-methyl-2-nitrobenzylidene)succinate. To asolution of 4-iodo-2-methyl-3-nitrobenzenamine (59 mmol) indimethylformamide (100 mL) was added diethyl itaconate (13.2 g, 71mmol), tetrabutylammonium chloride (16.4 g, 59 mmol), triethylamine (236mmol) and palladium acetate (675 mg, 3 mmol) under nitrogen. Thereaction mixture was heated to 80° C. for 2 h. The crude reactionmixture was then filtered, diluted with ether (250 mL), washed withwater (2×300 mL). The crude product was purified by flash chromatographyusing 20% ethyl acetate in hexane to give 8.5 g of the title compound.¹H NMR (500 MHz, CDCl₃): in δ 7.58 (s, 1 H), 7.10 (d, J=8.5 Hz, 1 H),6.73 (d, J=8.5 Hz, 1 H), 4.24-4.15 (m, 4 H), 3.40 (s, 2 H), 2.06 (s, 3H), 1.30-1.23 (m, 6 H).

Ethyl2-(7-amino-8-methyl-1-neopentyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate.To a solution of (E)-diethyl2-(4-amino-3-methyl-2-nitrobenzylidene)succinate (4.5 g, 13.4 mmol) inTHF (100 mL) was added (Boc)₂O (16 mmol) followed by catalytic amount ofdimethylaminopyridine (10 mg). The reaction mixture was heated in asealed tube for 3 h at 100° C. The reaction mixture was cooled, removedsolvent, diluted with ether and then washed with aqueous sodiumhydrogencarbonate (50 mL). The crude product was found to contain bothmono- and di-Boc protected compounds. The crude product was dissolved inmethanol (200 mL) and was added water (150 ml) followed by ammoniumchloride (14.3 g, 268 mmol) and iron powder (8.9 g, 160 mmol). Thereaction mixture was heated at 50° C. for 1 h, cooled and then filteredover a pad of celite. The solvent was removed, extracted with ethylacetate and then washed with brine and dried (Na₂SO₄). The crude productwas purified by flash chromatography using 30% ethyl acetate in hexaneas eluent to give the amine. The amine (4.1 g, 10 mmol) was dissolved indichloroethane (100 mL) followed by addition of acetic acid (10 mL),trimethylacetaldehyde (11 mmol) and magnesium sulfate (5.0 g). Thereaction mixture was stirred for 2 h and then filtered. To the filteredreaction mixture was added sodium triacetoxyborohydride (2.33 g, 11mmol) and stirring continued for additional 2 h. The reaction mixturewas diluted with hexane (150 mL), washed with water (2×100 mL), aqueousNaHCO₃ solution and dried (Na₂SO₄). The solvent was removed and thecrude product was dissolved in methanol (100 mL) followed by addition ofacetic acid (5 mL) and hydrogenated in a parr bottle at a pressure of 50psi hydrogen. The catalyst was removed by filtration and the solvent wasremoved. The crude product was dissolved in toluene (100 mL) followed byaddition of tosic acid (100 mg) and sodium cyanide (50 mg). The reactionmixture was refluxed for 12 h and the crude product was purified byflash chromatography using 50% ethyl acetate in hexane to give ethyl2-(7-amino-8-methyl-1-neopentyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate.MS (ESI) 333 (M+H); R_(f)=1.29.

2-(1-Neopentyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[3,4-h]quinolin-3-yl)aceticacid. To a solution of ethyl2-(7-amino-8-methyl-1-neopentyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate(170 mg, 0.51 mmol) in carbon tetrachloride (4.5 mL) was added aceticacid (0.5 mL) followed by isoamylnitrite (0.04 mL) and the reactionmixture was stirred for 2 h at room temperature. The reaction mixturewas diluted with dichloromethane (40 mL), washed with aqueous NaHCO₃ anddried. The solvent was removed and the crude product was dissolved inTHF (15 mL) followed by addition of lithium hydroxide (43 mg, 1 mmol)and water (5 mL). After stirring for 12 h, the solvent was removed,acidified with 6 M HCl and extracted with ethyl acetate to give2-(1-neopentyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[3,4-h]quinolin-3-yl)aceticacid. MS (ESI) 316 (M+H); R_(f)=1.31.

2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic aciddiethyl ester. 2-(S)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinicacid diethyl ester (3.0 g, 8.2 mmol) was dissolved in acetonitrile (40mL). Mixture was warmed to 60° C. N-Chlorosuccinimide (1.29 g, 9.7 mmol)was added to the warm solution. Reaction mixture was heated at refluxfor 10 minutes. Mixture was cooled to room temperature then diluted withethyl acetate (20 mL). Mixture was washed successively with saturatedaqueous sodium bicarbonate (40 mL), and brine (20 mL). Organic was dried(magnesium sulfate), filtered and concentrated in vacuo. Silica gelchromatography (ethyl acetate-hexanes) afforded the desired product in59% yield as an amber oil. ¹H NMR (300 MHz, CDCl₃): δ 6.98 (s, 1H), 5.15(d, J=3.3, 2H), 4.09 (m, 4H), 2.99 (m, 2H), 2.69 (m, 2H), 2.39 (dd,J1=4.8, J2=16.5, 1H), 2.17 (s, 3H), 2.06 (s, 3H), 1.20 (m, 6H). MS m/e(M−C₂H₄O₂+H)⁺=340.0.

2-(S)-(4-Acetoxymethyl-7-chloro-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester. Isoamyl nitrite (700 μL, 5.2 mmol), was added dropwise toan ice cold solution of2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic aciddiethyl ester (1.91 g, 4.8 mmol) in 5% acetic acid in tolune (81.2 mL).Mixture stirred at 0° C. for 45 minutes. Potassium acetate (1.50 g, 15.3mmol) was added to the mixture. Reaction was stirred at room temperaturefor 14 hours. Mixture was quenched with water. Mixture was extractedwith ethyl acetate (30 mL). Mixture was washed 2× saturated aqueoussodium bicarbonate. Organic was dried (magnesium sulfate) filtered andconcentrated. Silica gel chromatography (ethyl acetate-hexanes) affordedthe desired product in 80% yield as an amber oil. ¹H NMR (300 MHz,CDCl₃): δ=8.23 (s, 1H), 7.26 (s, 1H), 5.45 (s, 2H), 4.09 (q, J=7.0, 4H),3.20 (dd, J1=7.32, J2=13.2, 1H), 3.10 (m, 1H), 2.97 (dd, J1=7.0,J2=13.3, 1H), 2.73 (dd, J1=8.4, J2=16.8, 1H), 2.44 (dd, J1=5.5, J2=16.8,1H), 2.08 (s, 3H), 1.18 (m, 6H). MS m/e (M+H)⁺=411.0.

(S)-Dimethyl2-((7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate.2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic aciddiethyl ester (2.21 g, 5.4 mmol) was converted to the title compound ina manner analogous to the preparation of2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester. Material was obtained as amber solid in 99% yield. MS m/e(M+H)⁺=241.2.

(S)-Dimethyl2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate.(S)-Dimethyl2-((7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (2.0 g,5.9 mmol) was dissolved in dichloromethane (35 mL). Thionyl chloride(5.0 mL) was added to the mixture. Reaction stirred at room temperaturefor 1.5 hours. Mixture was concentrated. Residue was dissolved in ethylacetate. Mixture was washed twice with aqueous sodium bicarbonate andonce with brine. Organic was dried (magnesium sulfate), filtered andconcentrated in vacuo. Title compound was obtained as amber solid in 89%yield. MS m/e (M+H)⁺=359.1.

(S)-Methyl2-(4-chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate.(S)-Dimethyl2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (120 mg,0.33 mmol) was dissolved in DMF (1.0 mL). 4-Aminomethylpyridine (100 μL,1.0 mmol) was added to the mixture. Reaction stirred at room temperaturefor 24 hours. Mixture was diluted with ethyl acetate. Mixture was washedtwice with water and once with brine. Organic was dried (magnesiumsulfate), filtered and concentrated in vacuo. Residue was dissolved intoluene (4 mL). Acetic acid (1 mL) was added to the mixture. Reactionwas heated at reflux for 3.5 hours. Mixture was cooled to roomtemperature then diluted with ethyl acetate. Material was washed oncewith water and twice with aqueous sodium bicarbonate. Aqueous was madebasic with sodium bicarbonate. Back extracted from the aqueous twicewith ethyl acetate. Combined organics were dried (magnesium sulfate),filtered and concentrated in vacuo. Residue was purified with silica gelchromatography eluting dichloromethane and 2N ammonia in methanol. Titlecompound was obtained as yellow solid in 48% yield. MS m/e (M+H)⁺=399.2.

(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid dihydrochloride. (S)-Methyl2-(4-chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate(21 mg, 0.05 mmol) was dissolved in 1N hydrochloric acid (1.0 mL).Reaction was heated at 50° C. for 5 hours. Another 1 mL of 1Nhydrochloric acid was added to the mixture. Reaction was heated at 50°C. for 17 hours. Mixture was concentrated in vacuo. Residue was treatedwith acetonitrile and then the material was concentrated. Title compoundwas obtained as dark yellow solid in 83% yield. MS m/e (M+H)⁺=385.2.

(S)-Methyl2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate.(S)-Dimethyl2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (250 mg,0.63 mmol) and (1H-imidazol-2-yl)methanamine dihydrochloride (170 mg,1.0 mmol) were combined and suspended in acetonitrile (10 mL).Triethylamine (800 μL, 5.7 mmol) was added to the mixture. Reaction waswarmed to reflux for 3 hours. Acetic acid (1.5 mL) was added to themixture. Reaction was heated at reflux for 20 hours. Mixture was cooledto room temperature then diluted with dichloromethane. Mixture wasextracted twice with water. Aqueous layer was concentrated in vacuo.Residue was purified by preparatory HPLC. Water was lyophilized off.Remaining residue was passed through a column of Dowex 1x4-200 ionexchange resin eluting methanol. Title compound was recovered as amberresidue in 24% yield. MS m/e (M+H)⁺=388.1.

5-Amino-2-iodo-4-methybenzyl alcohol. To an ice cooled solution of3-amino-4-methylbenzyl alcohol (10.0 g, 72.9 mmol) in methanol (200 mL)1M iodinemonochloride in dichloromethane (80.0 mL, 80.0 mmoles) wasadded drop-wise over 30 minutes. Ice bath was removed. Reaction wasstirred at ambient temperature for 40 minutes. Mixture was concentratedin vacuo. Residue was treated with dichloromethane (250 mL). Solids werefiltered off and washed with dichloromethane. Solids were partitionedbetween ethyl acetate and 1N aqueous sodium hydroxide. Layers werepartitioned. Organic layer was washed with 1N aqueous sodium hydroxide.The combined aqueous layers were back extracted two times with ethylacetate. Combined organic layers were washed with brine. Combinedextracts were dried (magnesium sulfate), filtered and concentrated invacuo. Desired product was obtained as tan solid in 81% yield. MS m/e(M+H)⁺=264.

tert-Butyl 5-(hydroxymethyl)-4-iodo-2-methylphenylcarbamate.5-Amino-2-iodo-4-methybenzyl alcohol (4.60 g, 17.5 mmoles) was dissolvedin tetrahydrofuran (80 mL). Di-tert-butyl dicarbonate (5.30 g, 24.3mmoles) was added to the mixture. Reaction was heated at 60° C. for 20hours. Mixture was concentrated. Residue was purified by silica gelchromatography eluting ethyl acetate-hexanes. Title compound wasobtained as off-white solid. MS m/e (M−C₄H₈O+H)⁺=290.

5-(tert-Butoxycarbonyl)-2-iodo-4-methylbenzyl acetate. tert-Butyl5-(hydroxymethyl)-4-iodo-2-methylphenylcarbamate (4.32 g, 11.9 mmol) wasdissolved in dichloromethane (60 mL). Acetic anhydride (2.6 mL, 27.6mmol) was added to the mixture followed by potassium acetate (2.0 g,20.4 mmol). Reaction was stirred at room temperature over 15 hours.Mixture was warmed to 50° C. and held for 1 hour. Mixture was cooled toroom temperature then diluted with dichloromethane. Mixture was washedtwice with water, and once with saturated aqueous sodium bicarbonate.Organic layer was dried (magnesium sulfate), filtered and concentratedin vacuo. Residue was treated with 10% ethyl acetate-hexanes (100 mL).Material was concentrated in vacuo. Desired compound was obtained aswhite solid in 98% yield. ¹H NMR (300 MHz, CD₃OD): δ=7.64 (s, 1H), 7.54(s, 1H), 4.51 (s, 2H), 2.19 (s, 3H), 1.51 (s, 9H).

3-(2-Acetoxymethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester. Title compound was prepared in a manner analogous tothe preparation of3-(2-Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester. Material was obtained as a white solid in 65% yield.MS m/e (M+H)⁺=513.

3-(2-Acetoxymethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester. Title compound was prepared in a manner analogous tothe preparation of2-(S)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester. Material was obtained as clear colorless oil in 99%yield. MS m/e (M−H)⁻=513.

3-(2-Hydroxymethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester. Title compound was obtained in a manner analogous tothe preparation of2-(R)-Benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionicacid methyl ester. Material was obtained as white solid in 94% yield.

3-(2-Chloromethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester.3-(2-Hydroxymethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester (510 mg, 1.1 mmol) was dissolved in dichoromethane (5mL). Triethylamine (250 μL, 1.8 mmol ) was added to the mixture followedby methanesulfonyl chloride (100 μL, 1.3 mmol). Mixture was stirred atroom temperature for 1.5 hours. Mixture was diluted with dichloromethanethen washed once with water, twice with 1N hydrochloric acid, and oncewith brine. Organics were dried (magnesium sulfate), filtered andconcentrated in vacuo. Title compound was obtained as white solid in 91%yield. MS m/e (M+H)⁺=491.

(R)-Benzyl8-tert-butoxycarbonylamido-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-ylcarbamate.3-(2-Chloromethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester (335 mg, 0.72 mmol) was dissolved in acetonitrile (10mL). Potassium carbonate (220 mg, 1.6 mmol) was added to the mixturefollowed by benzylamine (150 μL, 1.4 mmol). Reaction was heated toreflux for 4.5 hours. Mixture was cooled to room temperature. Mixturewas filtered over celite. Filtrate was concentrated. Residue wasdissolved in toluene (15 mL). Acetic acid (100 μL) was added to themixture. Reaction was heated at reflux for 3 hours. Mixture was cooledto room temperature. Mixture was concentrated. Residue was purified bysilica gel chromatography eluting ethyl acetate-hexanes. Title compoundwas obtained as clear colorless oil in 81% yield. MS m/e (M+H)⁺=530.

(R)-tert-Butyl4-amino-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate.(R)-Benzyl8-tert-butoxycarbonylamido-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-ylcarbamate(305 mg, 0.58 mmol) was dissolved in methanol. A catalytic amount of 10%palladium on carbon was added to the mixture. Reaction was placed on aParr apparatus under 50 psi of hydrogen gas. Reaction shook at roomtemperature for 1 hour. Reaction was removed from the apparatus.Catalyst was filtered off. Filtrate was concentrated in vacuo. Titlecompound was obtained as clear colorless oil in 97% yield. MS m/e(M+H)⁺=396.

(R)-tert-Butyl2-benzyl-7-methyl-3-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamido)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate.(R)-tert-Butyl4-amino-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate(155 mg, 0.39 mmol) was dissolved in dichloromethane (10 mL). Aqueoussodium bicarbonate (10 mL) was added to the mixture. A solution of 20%phosgene in toluene (230 μL, 0.43 mmol) was added to the mixture withvigorous stirring. Reaction stirred at room temperature for 20 minutes.4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine acetate (140 mg,0.48 mmol) was added to the mixture. Reaction stirred at roomtemperature for 1 hour. Reaction layers were partitioned. Organic layerwas washed successively with 1N hydrochloric acid and brine. Organic wasdried (magnesium sulfate), filtered and concentrated in vacuo. Titlecompound was obtained as off-white solid in 94% yield. MS m/e(M+H)⁺=653.

(R)-Benzyl8-tert-butoxycarbonylamido-2-benzyl-9-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-ylcarbamate.3-(2-Chloromethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester was reacted in a manner analogous to the preparationof (R)-benzyl8-tert-butoxycarbonylamido-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-ylcarbamate.Title compound was obtained as white solid in 78% yield. MS m/e(M+H)⁺=530.

(R)-tert-Butyl4-amino-2-benzyl-9-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate.(R)-Benzyl8-tert-butoxycarbonylamido-2-benzyl-9-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-ylcarbamatewas reacted in a manner analogous to the preparation of (R)-tert-butyl4-amino-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate.Title compound was obtained as clear colorless oil in 99% yield. MS m/e(M+H)⁺=340.

(R)-tert-Butyl2-benzyl-9-methyl-3-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamido)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate.(R)-tert-Butyl4-amino-2-benzyl-9-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamatewas reacted in a manner analogous to the preparation of (R)-tert-butyl2-benzyl-7-methyl-3-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamido)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate.Title compound was obtained as off-white solid in 94% yield.

(R)-Benzyl1-acetyl-8-benzyl-7-oxo-1,5,6,7,8,9-hexahydroazepino[4,3-f]indazol-6-ylcarbamate.3-(2-Chloromethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester (160 mg, 0.33 mmol) was dissolved in dichloromethane(3 mL). Trifluoroacetic acid (1 mL) was added to the mixture. Reactionwas stirred at room temperature for 45 minutes. Mixture was concentratedto a yellow oil. Residue was dissolved in chloroform (3 mL). Acetic acid(100 μL) was added to the mixture followed by isoamyl nitrite (50 μL,0.37 mmol) then potassium acetate (65 mg, 0.66 mmol). Reaction washeated at reflux for 30 minutes. Mixture was cooled to room temperaturethen diluted with dichloromethane. Mixture was washed once with water,and twice with aqueous sodium bicarbonate. Organics were dried(magnesium sulfate), filtered and concentrated in vacuo. Reside wasdissolved in acetonitrile (3 mL). Benzylamine (100 μL, 0.92 mmol) wasadded to the mixture followed by potassium carbonate (50 mg, 0.36 mmol).Reaction was heated at reflux for 1 hour. Mixture was cooled to roomtemperature. Solids were filtered. Filtrate was concentrated in vacuo.Residue was treated with toluene (3 mL) and acetic acid (100 μL).Reaction was heated at reflux for 1 hour. Mixture was cooled to roomtemperature. Acetic anhydride (1 mL) was added to the mixture. Reactionwas stirred at room temperature for 1 hour. Mixture was concentrated.Residue was purified by silica gel chromatography eluting ethylacetate-hexanes. Title compound was obtained as amber oil in 27% yield.MS m/e (M+H)⁺=483.

(R)-benzyl8-oxo-9-(piperidin-4-yl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamatemethanesulfonate.4-(7-(R)-Benzyloxycarbonylamino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylicacid tert-butyl ester (100 mg, 0.19 mmol) was dissolved indichloromethane (2 mL). Anisole (100 μL, 0.92 mmol) was added to themixture followed by methanesulfonic acid (200 μL). Reaction stirred atroom temperature for 30 minutes. Mixture was diluted with diethyl ether,and the mixture stirred at room temperature for 30 minutes. Solventswere decanted off. Residue was dried in vacuo. Title compound wasobtained as dark oil in quantitative yield. MS m/e (M+H)⁺=434.

(R)-benzyl9-(1-acetylpiperidin-4-yl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate.(R)-benzyl8-oxo-9-(piperidin-4-yl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamatemethanesulfonate (100 mg, 0.19 mmol) was dissolved in a mixture ofdichloromethane (4 mL) and triethylamine (500 μL, 3.6 mmol). Aceticanhydride (500 μL, 5.3 mmol) was added to the mixture. Reaction stirredat room temperature overnight. Reaction mixture was washed successively1× water, 2× 1N hydrochloric acid, 2× 1N sodium hydroxide, and 1× brine.Organic was dried (magnesium sulfate), and filtered. Filtrate wasconcentrated in vacuo. Residue was treated with methanol (3 mL).Potassium carbonate (40 mg, 0.29 mmol) was added to the mixture.Reaction stirred at room temperature for 2 hours. Reaction was quenchedwith 1N hydrochloric acid (6 mL). Methanol was removed from the mixturein vacuo. Remaining aqueous mixture was made basic with sodiumbicarbonate. Mixture was extracted with ethyl acetate. Organic layer wasdried (magnesium sulfate), filtered and concentrated. Title compound wasobtained as yellow solid in 43% yield. MS m/e (M+H)⁺=476.

(R)-9-(1-acetylpiperidin-4-yl)-7-amino-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-onemethanesulfonate. (R)-benzyl9-(1-acetylpiperidin-4-yl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate(38 mg, 0.08 mmol) was dissolved in dichloromethane (1 mL). Anisole (30μL, 0.27 mmol) was added to the mixture followed by methanesulfonic acid(250 μL). Reaction stirred at room temperature for 2 hours. Mixture wasdiluted with diethyl ether. Mixture sat at room temperature for 30minutes. Solvents were decanted off. Remaining residue was dried invacuo. Title compound was obtained as dark oil in quantitative yield. MSm/e (M+H)⁺=342.

tert-butyl3-((R)-7-(benzyloxycarbonyl)-8-oxo-7,8-dihydroazepino[3,4-e]indazol-9(3H,6H, 10H)-yl)pyrrolidine-1-carboxylate.2-(R)-Benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester hydrochloride (150 mg, 0.31 mmol) andR,S-3-amino-1-N-Boc-pyrrolidine (90 μL, 0.48 mmol) were reacted in amanner analogous to the preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Title compound was obtained without purification asdark foam in 96% yield. MS m/e (M+H)⁺=342.

tert-butyl3-((R)-8-oxo-7-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamido)-7,8-dihydroazepino[3,4-e]indazol-9(3H,6H, 10H)-yl)pyrrolidine-1-carboxylate. tert-butyl3-((R)-7-(benzyloxycarbonyl)-8-oxo-7,8-dihydroazepino[3,4-e]indazol-9(3H,6H,10H)-yl)pyrrolidine-1-carboxylatewas dissolved in methanol (10 mL). Acetic acid (300 μL) was added to themixture followed by 10% palladium on carbon. Reaction vessel was placedon a Parr apparatus and charged with 30 psi of hydrogen gas. Reactionshook at ambient temperature for 2 hours. Reaction mixture was filtered.Filtrate was concentrated in vacuo. Residue was dissolved indichloromethane (2 mL). Triethylamine (500 μL, 3.6 mmol) was added tothe mixture followed by N,N′-disuccinimidyl carbonate (90 mg, 0.35mmol). Reaction stirred at room temperature for 30 minutes.3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one acetate (80 mg, 0.27mmol) was added to the mixture. Reaction stirred at room temperature for1 hour. Mixture was diluted with dichloromethane. Mixture was washedwith water. Organic layer was concentrated. C18 preparative HPLCpurification afforded the title compound as yellow solid in 24% yield.MS m/e (M−C₅H₈O₂+H)⁺=543.

3-(tert-butoxycarbonyl)-2-methyl-6-((2-oxo-2,5-dihydrofuran-3-yl)methyl)benzyacetate. Acetic acid 3-tert-butoxycarbonylamino-6-iodo-2-methyl-benzylester (575 mg, 1.4 mmol) was dissolved in N,N-dimethylformamide (2.5mL). α-Methylene-γ-butyrolactone (190 μL, 2.2 mmol) was added to themixture followed by potassium acetate (420 mg, 4.3 mmol), and thenpalladium(II) acetate (16 mg, 0.07 mmol). Reaction mixture was heated at80° C. for 26 hours. Mixture was cooled to room temperature andpartitioned between ethyl acetate and aqueous sodium bicarbonate. Layerswere separated. Organic layer was dried (magnesium sulfate), filteredand concentrated in vacuo. Silica gel chromatography afforded the titlecompound as off-white solid in 54% yield. MS m/e (M−H)⁻=374.

(S)-3-(tert-butoxycarbonyl)-2-methyl-6-((2-oxo-tetrahydrofuran-3-yl)methyl)benzylacetate.3-(tert-butoxycarbonyl)-2-methyl-6-((2-oxo-2,5-dihydrofuran-3-yl)methyl)benzylacetate (280 mg, 0.75 mmol) was dissolved in a mixture of ethyl acetate(10 mL) and methanol (10 mL). A catalytic amount of(−)-1,2-bis((2R,5R)-diethylphospholano)benzene(cyclooctadiene)rhodium(I) tetrafluoroborate was added to the mixture. Reaction vessel wasplaced on a Parr apparatus and charged with 50 psi of hydrogen gas.Reaction shook at room temperature for 16 hours. A fresh portion of(−)-1,2-bis((2R,5-diethylphospholano)benzene(cyclooctadiene)rhodium (I)tetrafluoroborate was added to the mixture. Reaction vessel was chargedwith 50 psi of hydrogen gas. Reaction shook at room temperature for 24hours. Reaction mixture was concentrated in vacuo. Residue was passedthrough a plug of silica gel eluting 80% ethyl acetate-hexanes. Filtratewas concentrated in vacuo. Title compound was obtained as clearcolorless oil in 69% yield. MS m/e (M−H)⁻=376.

(S)-3-((4-(hydroxymethyl)-1H-indazol-5-yl)methyl)-dihydrofuran-2(3H)-one.(S)-3-(tert-butoxycarbonyl)-2-methyl-6-((2-oxo-tetrahydrofuran-3-yl)methyl)benzylacetate (190 mg, 0.50 mmol) was dissolved in dichloromethane (4 mL).Trifluoroacetic acid (1 mL) was added to the mixture. Reaction stirredat room temperature for 30 minutes. Mixture was diluted withdichloromethane and then concentrated in vacuo. Residue was dissolved inchloroform (5 mL). Acetic acid (250 μL) was added to the mixturefollowed by isoamyl nitrite (80 μL, 0.60 mmol). Reaction stirred at roomtemperature for 20 minutes. Potassium acetate (400 mg, 4.1 mmol) wasadded to the mixture. Reaction stirred at room temperature for 1 hour.Mixture was diluted with dichloromethane. Mixture was washedsuccessively 1× water, 2× aqueous sodium bicarbonate. Organic layer wasdried (magnesium sulfate), filtered and concentrated in vacuo. Residuewas dissolved in methanol (5 μL). Potassium carbonate (120 mg, 0.87mmol) was added to the mixture. Reaction stirred at room temperature for1 hour. Reaction was quenched with 1N hydrochloric acid. Methanol wasremoved from the mixture in vacuo. Remaining aqueous was extracted 2×diethyl ether, made basic with sodium bicarbonate, and then extractedagain 2× diethyl ether. Combined extracts were dried (magnesiumsulfate), filtered, and concentrated in vacuo. Title compound wasobtained as amber oil in 73% yield. MS m/e (M+H)⁺=247.

(S)-2-(9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)ethylacetate.(S)-3-((4-(hydroxymethyl)-1H-indazol-5-yl)methyl)-dihydrofuran-2(3H)-one(70 mg, 0.28 mmol), was dissolved in dichloromethane (1.5 mL). Thionylchloride (500 μL) was added to the mixture. Reaction stirred at roomtemperature for 45 minutes. Mixture was concentrated. Residue wastreated with dichloromethane and re-concentrated. Residue was dissolvedin acetonitrile (3 mL). Potassium carbonate (150 mg, 1.1 mmol) was addedto the mixture followed by neopentylamine (100 μL, 0.85 mmol). Mixturewas heated at reflux for 45 minutes. Mixture was cooled to roomtemperature and filtered. Filtrate was concentrated in vacuo. Residuewas dissolved in toluene (5 mL). Acetic acid (200 μL) was added to themixture. Reaction was heated at reflux for 5.5 hours. Mixture wasconcentrated in vacuo. Preparatory HPLC purification gave the titlecompound as yellow solid in 19% yield. MS m/e (M−H)⁻=356.

(S)-7-(2-hydroxyethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(S)-2-(9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)ethylacetate (18 mg, 0.05 mmol) was dissolved in methanol (1 mL). Potassiumcarbonate (20 mg, 0.14 mmol) was added to the mixture. Reaction stirredat room temperature for 1 hour. Amberlite IRC-50 ion exchange resin wasadded to the mixture. Reaction stirred at room temperature for 15minutes. Mixture was filtered. Filtrate was concentrated in vacuo. Thetitle compound was obtained as yellow residue in 94% yield. MS m/e(M+H)⁺=316.

1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. Isonipecotic acid(1.05 g, 8.1 mmol) was suspended in a mixture of tetrahydrofuran (20 mL)and 1N sodium hydroxide (20 mL). Di-tert-butyl dicarbonate was added tothe mixture. Reaction stirred at room temperature for 2.5 hours. Mixturewas made acidic with 1N hydrochloric acid. Mixture was extracted 2×ethyl acetate. Combined organics were washed with brine and then dried(magnesium sulfate), filtered and concentrated in vacuo. Title compoundwas obtained as white solid in 94% yield. MS m/e (M−H)⁻=228.0.

tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate.tert-Butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (640 mg,2.8 mmol) and o-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (1.0 g, 3.1 mmol) were combined and dissolved inN,N-dimethylformamide (12 mL). N,N-Diisopropylethylamine was added tothe mixture. Reaction stirred at room temperature for 45 minutes.N,O-Dimethylhydroxylamine hydrochloride (450 mg, 4.6 mmol) was added tothe mixture. Reaction stirred at room temperature for 1.5 hours. Mixturewas diluted with diethyl ether and then washed 3× water, 1× 1Nhydrochloric acid. Organic layer was dried (magnesium sulfate), filteredand concentrated in vacuo. Title compound was obtained as clearcolorless oil in 70% yield. MS m/e (M−C₄H₈+H)⁺=217.1.

Acetophenone oxime. Acetophenone (5.0 mL, 43 mmol) was dissolved inmethanol (50 mL). Hydroxylamine hydrochloride (6.1 g, 88 mmol) was addedto the mixture followed by 10N sodium hydroxide (10 mL, 100 mmol).Reaction was stirred at room temperature for 20 minutes. 10N Sodiumhydroxide (5 mL, 50 mmol) was added to the mixture. Reaction was heatedat reflux for 1 hour. Mixture was cooled to room temperature and stirredfor 4 hours. Reaction mixture was concentrated in vacuo. Residue wastreated with water. Mixture was extracted 2× diethyl ether. Combinedextracts were washed 1× water, 1× brine. Organic layer was dried(magnesium sulfate), filtered and concentrated. Title compound wasobtained as white solid in 76% yield. MS m/e (M+H)⁺=136.0.

tert-Butyl4-(5-hydroxy-3-phenyl-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate.Acetophenone oxime (180 mg, 1.3 mmol) was dissolved in tetrahydrofuran(15 mL). Mixture was cooled to 0° C. 2.0M Butyllithium in pentanes (1.35mL, 2.7 mmol) was added to the mixture drop-wise. Reaction stirred at 0°C. for 1 hour. A solution of tert-Butyl4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (360 mg, 1.3 mmol)in tetrahydrofuran (5 mL) was added to the reaction mixture drop-wise.Reaction stirred at 0° C. for 1 hour. Reaction was quenched with aqueousammonium chloride. Mixture was extracted 2× ethyl acetate. Combinedextracts were dried (magnesium sulfate), filtered and concentrated invacuo. Silica gel chromatography afforded the title compound as clearcolorless oil in 71% yield. MS m/e (M−H)⁻=345.1.

tert-Butyl 4-(3-phenylisoxazol-5-yl)piperidine-1-carboxylate. tert-Butyl4-(5-hydroxy-3-phenyl-4,5-dihydroisoxazol-5-yl)piperidine-1-carboxylate(320 mg, 0.92 mmol) was dissolved in methanol (10 mL). A solution ofsodium carbonate (200 mg, 1.9 mmol) in water (10 mL) was added to themixture. Reaction was stirred at reflux for 2 hours. Methanol wasremoved from the reaction mixture in vacuo. Remaining aqueous wasextracted 2× ethyl acetate. Combined extracts were washed with brine.Organic layer was dried (magnesium sulfate), filtered, and concentrated.Title compound was obtained as off-white solid in 86% yield.(M−C₄H₈+H)⁺=273.1.

4-(3-Phenylisoxazol-5-yl)piperidine. tert-Butyl4-(3-phenylisoxazol-5-yl)piperidine-1-carboxylate (225 mg, 0.78 mmol)was diluted in dichloromethane (3 mL). Trifluoroacetic acid (3 mL) wasadded to the mixture. Reaction stirred at room temperature for 1 hour.Mixture was diluted with dichloromethane and then concentrated in vacuo.Residue was treated with aqueous sodium bicarbonate. Mixture wasextracted 2× ethyl acetate. Combined extracts were washed 1× water, 1×brine. Organic layer was dried (magnesium sulfate), filtered andconcentrated in vacuo. Title compound was obtained as white solid in 76%yield. MS m/e (M+H)⁺=229.1.

2-(R)-(Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester.2-(S)-(Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzylidene)-succinicacid diethyl ester (700 mg, 1.5 mmol) was hydrogenated in a manneranalogous to the preparation of2-(S)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester using(+)-1,2-bis((2S,5S)-diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethane sulfonate as the catalyst. Silica gel chromatographyafforded the title compound as lightly colored oil in 75% yield. MS m/e(M−H)⁻=464.0.

2-(R)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethylester. Trifluoroacetic acid (2.5 mL) was added to a solution of2-(R)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester (525 mg, 1.1 mmol) in dichloromethane (10 mL).Reaction mixture was stirred at room temperature for 1 hour. Mixture wasconcentrated in vacuo. Residue was treated with aqueous sodiumbicarbonate and extracted with ethyl acetate (2×20 mL). Combined organiclayers were dried (magnesium sulfate), filtered and concentrated invacuo. The title compound was obtained as amber oil in 99% yield. MS m/e(M−C₂H₄O₂+H)³⁰ =306.1.

2-(R)-(4-Acetoxymethyl-1H-indazol-5-ylmethyl)-succinic acid diethylester. Isoamyl nitrite (170 μL, 1.3 mmol) was added dropwise to a cooled(water ice bath) solution of2-(R)-(2-acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethylester in 5% acetic acid—chloroform (5 mL). Mixture was stirred at 0° C.for 1.5 hours. Mixture was diluted with dichloromethane (20 mL) and thenwashed with saturated aqueous sodium bicarbonate (2×20 mL). Organic wasdried (magnesium sulfate), filtered and concentrated in vacuo. Titlecompound was obtained as amber oil in 99% yield. MS m/e (M+H)⁺=377.1.

2-(R)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester. Potassium carbonate (380 mg, 2.7 mmol) was added to a solution of2-(R)-(4-acetoxymethyl-1H-indazol-5-ylmethyl)-succinic acid diethylester (420 mg, 1.1 mmol) in methanol (10 mL). Mixture was stirred atroom temperature for 2 hours. Reaction was quenched with 1N hydrochloricacid. Methanol was removed from the mixture in vacuo. Remaining aqueousmade basic with sodium bicarbonate. Mixture was extracted with ethylacetate (2×20 mL). Combined organic layers were washed successively withwater (20 mL) and brine (20 mL). Organic was dried (magnesium sulfate),filtered and concentrated in vacuo. Title compound was obtained as amberoil in 92% yield. MS m/e (M+H)⁺=307.1.

[9-(2,2-Dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Thionyl chloride (2 mL) was added to a solution of2-(R)-(4-hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester (280 mg, 0.91 mmol) in dichloromethane (4 mL). Reaction wasstirred at room temperature for 1 hour. Mixture was diluted withdichloromethane and then concentrated in vacuo. Residue was suspended inacetonitrile (5 mL). Potassium carbonate (300 mg, 2.2 mmol) was added tothe mixture followed by neopentylamine (250 μL, 2.1 mmol). Reaction washeated at reflux for 30 minutes. Neopentylamine (150 μL, 1.3 mmol) wasadded to the mixture. Reaction was heated at reflux for 20 minutes.Mixture was cooled to room temperature and filtered. Filtrate wasconcentrated in vacuo. Residue was dissolved in toluene (5 mL). Aceticacid (300 μL) was added to the mixture. Reaction was heated at refluxfor 16 hours. Mixture was cooled to room temperature and diluted withethyl acetate. Mixture was washed successively with aqueous sodiumbicarbonate (2×), water, and brine. Organic layer was dried (magnesiumsulfate), filtered and concentrated in vacuo. Silica gel chromatographyafforded the title compound as amber oil in 29% yield. MS m/e(M−H)⁻=342.1.

[9-(2,2-Dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-aceticacid. Lithium hydroxide monohydrate (31 mg, 0.74 mmol) was added to asolution of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (90 mg, 0.26 mmol) in methanol (2.5 mL),tetrahydrofuran (2 mL) and water (2.5 mL). Reaction mixture was heatedat 50° C. for 1.5 hours. The organic solvents were removed from themixture in vacuo. Remaining aqueous was neutralized with 1 Nhydrochloric acid (730 μL). Mixture was extracted with ethyl acetate(2×20 mL). Combined organic layers were washed with brine (20 mL) andthen dried (magnesium sulfate), filtered and concentrated in vacuo.Title compound was obtained as amber solid in 88% yield. MS m/e(M−H)⁻=328.1.

tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate. 60%sodium hydride in mineral oil (7.92 g, 198.02 mmoles) was washed withhexanes then suspended in N,N-dimethylformamide (220.00 mL). The mixturewas cooled to 0° C. Trimethyl phosphonoacetate (29.0 mL, 189.82 mmoles)was added drop-wise to the reaction. The mixture was held at 0° C. withstirring on and held for 20 min. A solution ofN-tert-butoxycarbonyl-4-piperidone (30.41 g, 152.62 mmoles) in 80 mLN,N-dimethylformamide was added to the mixture drop-wise. Reaction wasstirred at room temperature for 3 hours. Mixture was diluted withdiethyl ether (650 mL). Mixture was washed once with water. Aqueouslayer was back extracted once with diethyl ether. Organic layers werecombined. The mixture was washed 4 times with water and the aqueousphase was discarded. The mixture was washed with brine and the aqueousphase was discarded. The material was dried over MgSO4, filtered, andconcentrated to dryness. Title compound was obtained as white solid in92% yield. ¹H NMR (300 MHz, CDCl₃): δ=5.68 (s, 1H), 3.66 (s, 3H),3.40-3.51 (m, 4H), 2.90 (t, J=5.49, 2H), 2.25 (t, J=5.49, 2H), 1.44 (s,9H).

tert-Butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate. tert-Butyl4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (35.71 g, 140mmol) was dissolved in a mixture of ethyl acetate (110 mL) and methanol(110 mL). 50% wet 10% palladium on carbon (3.3 g) was added to themixture. Reaction vessel was charged with 55 psi of hydrogen gas.Reaction shook on a Parr apparatus at room temperature for 16 hours.Reaction mixture was filtered to remove the catalyst. Filtrate wasconcentrated in vacuo. Title compound was obtained as clear colorlessoil in 97% yield. ¹H NMR (300 MHz, CDCl₃): δ=4.04 (d, J=10.25, 2H), 3.64(s, 3H), 2.68 (t, J=12.44, 2H), 2.21 (d, J=6.95, 2H), 1.98-1.77 (m, 1H),1.64 (d, J=13.5, 2H), 1.41 (s, 9H), 1.25-0.99 (m, 2H).

tert-butyl4-(1-methoxy-3-(2-nitrophenyl)-1-oxopropan-2-yl)piperidine-1-carboxylate.tert-Butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (240 mg,0.93 mmol) was dissolved in tetrahydrofuran (7 mL). Mixture was cooledto −78° C. A 0.5 M solution of potassium bistrimethylsilyl)amide intoluene (2.2 mL, 1.1 mmol) was added to the mixture drop-wise. Reactionstirred at −78° C. for 20 minutes. A solution of 2-nitrobenzylbromide(240 mg, 1.1 mmol) in tetrahydrofuran (2 mL) was added to the reactionmixture drop-wise. Reaction stirred at −78° C. for 40 minutes. Dry icebath was removed and the reaction mixture was allowed to warm to roomtemperature over 30 minutes. Reaction was quenched with aqueous ammoniumchloride. Mixture was extracted with ethyl acetate (2×20 mL). Combinedextracts were dried (magnesium sulfate), filtered and concentrated invacuo. Silica gel chromatography afforded the title compound as yellowoil in 41% yield. MS m/e (M−C₄H₈+H)⁺=337.3.

tert-Butyl4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperidine-1-carboxylate.tert-butyl4-(1-methoxy-3-(2-nitrophenyl)-1-oxopropan-2-yl)piperidine-1-carboxylate(660 mg, 1.7 mmol) was dissolved in a mixture of ethyl acetate (15 mL)and methanol (15 mL). Acetic acid (250 μL, 4.4 mmol) was added to themixture. A catalytic amount of 50% wet 10% palladium on carbon was addedto the mixture. Reaction vessel was charged with 15 psi of hydrogen gas.Reaction shook on a Parr apparatus at room temperature for 2 hours.Reaction mixture was filtered to removed the catalyst. Filtrated wasconcentrated in vacuo. Silica gel chromatography gave the title compoundas orange foam in 47% yield. MS m/e (M−H)⁻=329.1.

3-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one. Trifluoroacetic acid(3 mL) was added to a solution of tert-Butyl4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperidine-1-carboxylate (260mg, 0.79 mmol) in dichloromethane (3 mL). Reaction stirred at roomtemperature for 1 hour. Reaction mixture was concentrated in vacuo.Residue was dissolved in methanol. Dowex 1x4-200 ion exchange resin wasadded to the mixture to create a slurry. Mixture stirred at roomtemperature for 30 minutes. Resin was filtered off and washed withmethanol. Filtrate was concentrated. Title compound was obtained as darkfoam in quantitative yield. MS m/e (M+H)⁺=231.1.

tert-Butyl 4-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate. Potassiumcarbonate (3.4 g, 25 mmol) was added to a mixture of N-Boc-piperazine(3.0 g, 16 mmol) in acetonitrile (20 mL). Methyl bromoacetate (1.5 mL,16 mmol) was added to the mixture. Reaction stirred at room temperaturefor 1.5 hours. Mixture was filtered over celite. Filtrate wasconcentrated in vacuo. Residue was treated with diethyl ether (10 mL),filtered and concentrated in vacuo. Bulb to bulb distillation (165° C.at 700 mtorr) gave the title compound as clear colorless oil in 60%yield. MS m/e (M+H)⁺=259.4.

tert-Butyl4-(1-methoxy-3-(2-nitrophenyl)-1-oxopropan-2-yl)piperazine-1-carboxylate.tert-Butyl 4-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (1.0 g, 3.9mmol) and 2-nitrobenzylbromide (1.0 g, 4.6 mmol) were reacted in amanner analogous to the preparation of tert-butyl4-(1-methoxy-3-(2-nitrophenyl)-1-oxopropan-2-yl)piperidine-1-carboxylate.Title compound was obtained as amber oil in 51% yield. MS m/e(M+H)⁺≦394.4.

tert-Butyl4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperazine-1-carboxylate.tert-Butyl4-(1-methoxy-3-(2-nitrophenyl)-1-oxopropan-2-yl)piperazine-1-carboxylate(770 mg, 2.0 mmol) was reacted in a manner analogous to the preparationof tert-butyl4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperidine-1-carboxylate. Titlecompound was obtained as amber oil in quantitative yield. MS m/e(M+H)₊=332.3.

3-(Piperazin-1-yl)-3,4-dihydroquinolin-2(1H)-one. tert-Butyl4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperazine-1-carboxylate (640mg, 1.9 mmol) was reacted in a manner analogous to the preparation of3-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one. Title compound wasobtained as light brown solid in quantitative yield. MS m/e(M+H)⁺=232.4.

Methyl 2-(2-(chloromethyl)phenyl)acetate. Hydrogen chloride gas wasbubbled though a solution of 3-isochromanone (1.2 g, 8.1 mmol) inmethanol (30 mL) for 3 minutes. Reaction stirred at room temperature for8 hours. Mixture was diluted with water (70 mL). Mixture was extractedwith dichloromethane (2×40 mL). Combined organic layers were washed withbrine (20 mL). Mixture was dried (magnesium sulfate), filtered andconcentrated in vacuo. Title compound was obtained as clear colorlessoil in 90% yield. ¹H NMR (300 MHz, CDCl₃): δ=7.40-7.26 (m, 4H), 4.67 (s,2H), 3.80 (s, 2H), 3.69 (s, 3H).

tert-Butyl4-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxylate.Potassium carbonate (1.4 g, 10 mmol) was added to a solution of methyl2-(2-(chloromethyl)phenyl)acetate (940 mg, 4.7 mmol) in acetonitrile (20mL). 4-Amino-N-Boc-piperidine (1.13 g, 5.6 mmol) was added to themixture. Reaction was heated at reflux for 1 hour. Mixture was cooled toroom temperature and then filtered over celite. Filtrate wasconcentrated in vacuo. Residue was treated with toluene (29 mL). Aceticacid (1.5 ml) was added to the mixture. Reaction was heated at refluxfor 2 hours. Mixture was concentrated in vacuo. Residue was treated withethyl acetate (50 mL). Mixture was washed successively with aqueoussodium bicarbonate (2×30 mL), 1N hydrochloric acid (30 mL), and brine(20 mL). Organic layer was dried (magnesium sulfate), filtered andconcentrated in vacuo. Silica gel chromatography gave the title compoundas lightly colored oil in 40% yield. MS m/e (M+H)⁺=331.2.

2-(Piperidin-4-yl)-1,2-dihydroisoquinolin-3(4H)-one. tert-Butyl4-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxylate (730mg, 2.2 mmol) was reacted in a manner analogous to the preparation of3-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one. Title compound wasobtained as yellow solid in 96% yield. MS m/e (M+H)⁺=231.4.

tert-Butyl 4-(quinolin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate.3-Quinolineboronic acid (250 mg, 1.4 mmol) and tert-butyl4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate(580 mg, 1.8 mmol) were combined and dissolved in a mixture of toluene(10 mL) and ethanol (1 mL). 2M aqueous sodium bicarbonate solution (1.5mL, 3.0 mmol) was added to the mixture followed by lithium chloride (180mg, 4.2 mmol). Nitrogen gas was bubbled through the mixture for 10minutes. Tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.07 mmol) wasadded to the mixture. Reaction was heated at reflux for 3.5 hours.Mixture was cooled to room temperature and diluted with ethyl acetate(50 mL). Mixture was washed successively with water (2×30 mL) and brine(20 mL). Organic layer was dried (magnesium sulfate), filtered andconcentrated in vacuo. Silica gel chromatography afforded the desiredproduct as lightly colored oil in 76% yield. MS m/e (M−C₄H₈+H)⁺=255.1.

3-(Piperidin-4-yl)quinoline. A catalytic amount of 50% wet 10% palladiumon carbon was added to a mixture of tert-butyl4-(quinolin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (260 mg, 0.84mmol) in methanol (10 mL). Reaction vessel was placed on a Parrapparatus and charged with 10 psi of hydrogen gas. Reaction shook atroom temperature for 4 hours. Mixture was filtered to removed catalyst.Filtrate was concentrated in vacuo. Residue was dissolved indichloromethane (4 mL). Trifluoroacetic acid (1 mL) was added to themixture. Reaction stirred at room temperature for 2 hours. Reactionmixture was concentrated in vacuo. Residue was dissolved indichloromethane (20 mL). Mixture was washed with aqueous sodiumbicarbonate (20 mL). Aqueous layer was back extracted withdichloromethane (30 mL). Organic layers were combined, dried (magnesiumsulfate), filtered and concentrated in vacuo. Title compound wasobtained as yellow oil in 45% yield. MS m/e (M+H)⁺=213.2.

Methyl 2-(methylsulfonamido)benzoate. Methanesulfonyl chloride (3.4 mL,44 mmol) was added to a solution of methyl acnthranilate (5.0 mL, 39mmol) in pyridine (10 mL, 124 mmol). Mixture stirred at room temperaturefor 16 hours. Reaction was quenched with 1N hydrochloroic acid (150 mL).Mixture was extracted with ethyl acetate (2×200 mL). Organic layers werewashed successively with 1N hydrochloric acid (2×100 mL) and brine (50mL). Organic layer was dried (magnesium sulfate), filtered andconcentrated in vacuo. Residue was crystallized from 50 mL isopropylalcohol. Solids were filtered, washed with isopropyl alcohol and driedin vacuo. Title compound was obtained as pink crystals in 75% yield. MSm/e (M−H)⁻=228.0.

Methyl 2-(N-benzylmethan-2-ylsulfonamido)benzoate. 60% Sodium hydride inmineral oil (650 mg, 16.3 mmol) was washed with hexanes and thensuspended in N,N-dimethylformamide (50 mL). Mixture was cooled to 0° C.A solution of methyl 2-(methylsulfonamido)benzoate (3.1 g, 13.5 mmol) inN,N-dimethylformamide (10 mL) was added to the mixture drop-wise withstirring. Reaction was held at 0° C. with stirring for 15 minutes.Benzylbromide (1.9 mL, 15.9 mmol) was added to the mixture drop-wise.Reaction was stirred at room temperature for 16 hours. Reaction wasquenched with 1N hydrochloric acid (50 mL). Mixture was extracted withdiethyl ether (2×50 mL). Organic layers were combined and washedsuccessively with water (2×50 mL) and brine (30 mL). Organic layer wasdried (magnesium sulfate), filtered and concentrated in vacuo. Silicagel chromatography afforded the title compound as clear colorless oil in76% yield. MS m/e (M−CH₄O+H)⁺=288.1.

1-Benzyl-2,2-dioxo-2,3-dihydro-1H-2,1-benzothiazin-4-one. 60% Sodiumhydride in mineral oil (500 mg, 12.5 mmol) was washed with hexanes andthen suspended in N,N-dimethylformamide (15 mL). Mixture was cooled to0° C. A solution of methyl 2-(N-benzylmethan-2-ylsulfonamido)benzoate(3.25g, 10.2 mmol) in N,N-dimethylformamide (20 mL) was added to themixture drop-wise. Mixture was warmed to room temperature. Reactionstirred at room temperature for 3 hours. Reaction was quenched with 1Nhydrochloric acid (40 mL). Mixture was extracted with diethyl ether(2×40 mL). Combined organic layers were washed with water (2×40 mL).Organic layer was dried (magnesium sulfate), filtered and concentratedin vacuo. Title compound was obtained as light yellow solid in 85%yield. MS m/e (M−H)⁻=286.1.

4-(2,2,4-Trioxo-1,2,3,4-tetrahydro-2,1-benzothiazin-3-yl)-piperidine-1-carboxylicacid tert-butyl ester.1-Benzyl-2,2-dioxo-2,3-dihydro-1H-2,1-benzothiazin-4-one (1.51 g, 5.26mmol) was dissolved in pyridine (50 mL).N-tert-Butoxycarbonyl-4-piperidinone (1.24 g, 6.33 mmol) was added tothe mixture followed by piperidine (110 μL, 1.11 mmol). Molecular sieveswere added to the mixture. Reaction stirred at room temperature for 40hours. Reaction mixture was filtered over celite. Filtrate wasconcentrated in vacuo. Residue was purified by silica gelchromatography. The major component was isolated and the fractionsconcentrated in vacuo. Residue was dissolved in methanol (50 mL). Acatalytic amount of 50% wet 10% palladium on carbon was added to themixture. Reaction vessel was placed on a Parr apparatus and charged with55 psi of hydrogen gas. Reaction shook at room temperature for 2 hours.Reaction mixture was filtered over celite. Fresh catalyst was added tothe filtrate. Reaction vessel was placed on a Parr apparatus and chargedwith 55 psi of hydrogen gas. Reaction shook at room temperature for 1hour. Mixture was filtered over celite. A third batch of fresh catalystwas added to the mixture. Reaction vessel was placed on a Parr apparatusand charged with 55 psi of hydrogen gas. Reaction shook at roomtemperature for 7.5 hours. Catalyst was filtered off. Filtrate wasconcentrated in vacuo. Silica gel chromatography afforded the titlecompound as pale yellow solid in 24% yield. MS m/e (M−H)⁻=379.1.

2,2-Dioxo-3-piperidin-4-yl-2,3-dihydro-1H-2,1-benzothiazin-4-onehydrochloride.4-(2,2,4-Trioxo-1,2,3,4-tetrahydro-2,1-benzothiazin-3-yl)-piperidine-1-carboxylicacid tert-butyl ester (175 mg, 0.46 mmol) was dissolved in 4M hydrogenchloride in 1,4-dioxane (3.0 mL, 12.0 mmol). Reaction stirred at roomtemperature for 45 minutes. Reaction mixture was concentrated to drynessin vacuo. Title compound was obtained as pink solid in quantitativeyield. MS m/e (M+H)⁺=281.1.

tert-Butyl4-(3-(2-ethoxy-2-oxoethyl)-3-phenylureido)piperidine-1-carboxylate.4-Amino-1-N-Boc-piperidine (760 mg, 3.79 mmol) was dissolved in amixture of dichloromethane (40 mL) and aqueous sodium bicarbonate (30mL). A solution of 20% phosgene in toluene (10 mL, 18.9 mmol) was addedto the mixture with vigorous stirring. Reaction stirred vigorously atroom temperature for 40 minutes. Reaction layers were partitioned.Organic layer was dried (magnesium sulfate), filtered and concentratedin vacuo. Residue was dissolved in toluene (30 mL). N-Phenylglycineethyl ester was added to the mixture. Reaction was heated at reflux for15 hours. Mixture was cooled to room temperature and diluted with ethylacetate (50 mL). Mixture was washed successively with 1N hydrochloricacid (3×50 mL) and brine (30 mL). Organic layer was dried (magnesiumsulfate), filtered and concentrated in vacuo. Silica gel chromatographyafforded the title compound as pale yellow solid in 63% yield. ¹H NMR(300 MHz, CDCl₃): δ=7.47-7.26 (m, 5H), 4.30 (s, 1H), 4.16 (q, J=7.32,2H), 3.88 (d, J=12.81, 2H), 3.81-3.69 (m , 1H), 2.80-2.70 (m, 2H), 1.83(dd, J1=12.62, J2=3.11, 2H), 1.38 (s, 9H), 1.23 (t, J=7.14, 3H),1.19-1.03 (m, 2H).

tert-Butyl4-(2,5-dioxo-4-phenylimidazolidin-1-yl)piperidine-1-carboxylate.Triethylamine (200 μL, 1.43 mmol) was added to a solution of tert-butyl4-(3-(2-ethoxy-2-oxoethyl)-3-phenylureido)piperidine-1-carboxylate (90mg, 0.22 mmol) in ethanol (1.8 mL). Reaction was held at 60° C. withstirring for 3 hours. Reaction mixture was concentrated in vacuo. Residewas treated with dichloromethane (20 mL) and then concentrated in vacuo.Title compound was obtained as white solid in 81% yield. MS m/e(M−C₄H₈+H)⁺=304.2.

5-Phenyl-3-(piperidin-4-yl)imidazolidine-2,4-dione hydrochloride.tert-Butyl4-(3-(2-ethoxy-2-oxoethyl)-3-phenylureido)piperidine-1-carboxylate (60mg, 0.17 mmol) was dissolved in 4M hydrogen chloride solution in1,4-dioxane (2.0 mL). Reaction stirred at room temperature for 30minutes. Solids were filtered off and washed with diethyl ether anddried. Title compound was obtained as white solid in quantitative yield.MS m/e (M+H)⁺=260.2.

Ethyl 3-formylpyridin-2-ylcarbamate. Diethyl pyrocarbonate (570 μL, 3.9mmol) was added to a solution of 2-aminopyridine-3-carboxaldehyde (400mg, 3.3 mmol) in benzene (20 mL). Mixture was warmed to 60° C. and heldfor 4 hours. Diethyl pyrocarbonate (1 mL, 6.8 mmol) was added to themixture. Reaction was warmed to 60° C. and held for 1 hour. Mixture wascooled to room temperature. Diethyl pyrocarbonate (1 mL, 6.8 mmol) wasadded to the mixture. Reaction stirred at room temperature for 16 hours.Mixture was concentrated in vacuo. Silica gel chromatography afforded totitle compound as white solid in 58% yield. MS m/e (M+H)⁺=195.1.

tert-Butyl4-(2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)piperidine-1-carboxylate.4-Amino-1-N-Boc-piperidine (290 mg, 1.4 mmol) was added to a solution ofethyl 3-formylpyridin-2-ylcarbamate (240 mg, 1.2 mmol) in methanol (10mL). Mixture was warmed to 60° C. and held for 1.5 hours. Mixture wascooled to room temperature. Sodium borohydride (62 mg, 1.6 mmol) wasadded to the mixture. Reaction stirred at room temperature for 30minutes. Toluene (20 mL) was added to the mixture followed by aceticacid (1.0 mL). Mixture was warmed to 110° C. Methanol was driven fromthe reaction mixture and collected in a Dean-Stark trap. Mixture washeld at 110° C. for 5 hours. Mixture was cooled to room temperature andheld for 16 hours. Reaction was quenched with aqueous sodiumbicarbonate. Mixture was extracted with ethyl acetate (2×30 mL).Combined organics were washed successively with water (30 mL) and brine(20 mL). Organic layer was dried (magnesium sulfate), filtered andconcentrated in vacuo. Silica gel chromatography afforded the titlecompound as white solid in 44% yield. MS m/e (M−H)⁻=311.2.

3-(Piperidin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-onedihydrochloride. A suspension of tert-butyl4-(2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)piperidine-1-carboxylate(220 mg, 0.66 mmol) in 4N hydrogen chloride in 1,4-dioxane (5.0 mL) wasstirred at room temperature for 45 minutes. Mixture was concentrated invacuo. Crystallization from ethanol and ethyl acetate afforded the titlecompound as white solid in 62% yield. (M+H)⁺=233.2.

[4-Chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid. 2-(S)-(4-acetoxymethyl-7-chloro-1H-indazol-5-ylmethyl)-succinicacid diethyl ester (530 mg, 1.48 mmol) and 2,2,2-trifluoroethylamine (1mL, 12.5 mmol) was reacted following reaction scheme and proceduresanalogous to the preparation of[4-Chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as white solid in 20% yield. MS m/e(M−H)⁻=374.0.

N-(3-Formylpyridin-2-yl)pivalamide. Triethlyamine (7.6 mL, 54 mmol), wasadded to a solution of 2-aminopyridine-3-carboxaldehyde (4.45 g, 36mmol) in dichloromethane (70 mL). Mixture was cooled to 0° C. A solutionof pivaloyl chloride (5.3 mL, 43 mmol) in dichloromethane (30 mL) wasadded to the mixture. Reaction was warmed to room temperature. Mixturestirred at room temperature for 63 hours. Mixture was washedsuccessively with water (2×50 mL) and brine (30 mL). Organic layer wasdried (magnesium sulfate), filtered and concentrated in vacuo. Silicagel chromatography afforded the title compound as off-white solid in 90%yield. (M+H)⁺=207.1.

tert-Butyl4-(1-hydroxy-3-methoxy-3-oxo-1-(2-pivalamidopyridin-3-yl)propan-2-yl)piperidine-1-carboxylate.A solution of diisoproplyamine (6.0 mL, 43 mmol) in tetrahydrofuran (200mL) was cooled to −78° C. A 2.5M solution of n-butyllithium in hexanes(17.0 mL, 43 mmol) was added to the mixture drop-wise. Mixture was heldat −78° C. with stirring for 20 minutes. A solution of tert-butyl4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (9.3 g, 36 mmol) intetrahydrofuran (35 mL) was added to the mixture drop-wise. Mixture washeld at −78° C. for 1.5 hours. In a separate flask, 60% sodium hydridein mineral oil (1.57 g, 39 mmol) was washed in hexanes and thensuspended in tetrahydrofuran (70 mL). Mixture was cooled to 0° C. Asolution of N-(3-formylpyridin-2-yl)pivalamide (6.74 g, 33 mmol) intetrahydrofuran (20 mL) was added to the mixture drop-wise. Reaction washeld at 0° C. with stirring for 2 hours. Mixture was warmed to roomtemperature and then added to the butyllithium containing solutiondrop-wise. Reaction mixture was held at −78° C. with stirring for 2hours. Mixture was allowed to slowly warm to room temperature. Mixturestirred at room temperature for 14 hours. Reaction was quenched withaqueous ammonium chloride. The mixture was extracted with ethyl acetate(2×100 mL). Organic extracts were combined, dried (magnesium sulfate),filtered and concentrated in vacuo. Silica gel chromatography affordedthe title compound as white foam in 93% yield. (M+H)⁺=464.2.

3-(Piperidin-4-yl)-1,8-naphthyridin-2(1H)-one dihydrochloride.Concentrated hydrochloric acid (25 mL, 305 mmol) was added with stirringto a mixture of tert-butyl4-(1-hydroxy-3-methoxy-3-oxo-1-(2-pivalamidopyridin-3-yl)propan-2-yl)piperidine-1-carboxylate(14.0 g, 30.2 mmol) and water (75 mL). Reaction was heated to reflux andheld for 25 hours. Mixture was concentrated in vacuo. Residue wascrystallized from ethanol. Title compound was obtained as white solid in33% yield. (M+H)⁺=230.2.

tert-Butyl4-(1-hydroxy-3-methoxy-3-oxo-1-(4-pivalamidopyridin-3-yl)propan-2-yl)piperidine-1-carboxylate.tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (1.33 g, 5.2mmol) and N-(3-formyl-4-pyridinyl-2,2-dimethylpropanamide (1.0 g, 4.7mmol) were reacted in a manner analogous to the preparation oftert-butyl4-(1-hydroxy-3-methoxy-3-oxo-1-(2-pivalamidopyridin-3-yl)propan-2-yl)piperidine-1-carboxylate.Title compound was obtained as white foam in 54% yield. (M+H)⁺=464.2.

3-(piperidin-4-yl)-1,6-naphthyridin-2(1H)-one. Concentrated hydrochloricacid (8.0 mL, 97 mmol) was added with stirring to a mixture oftert-butyl4-(1-hydroxy-3-methoxy-3-oxo-1-(4-pivalamidopyridin-3-yl)propan-2-yl)piperidine-1-carboxylate(1.2 g, 2.6 mmol) and water (24 mL). Reaction was heated to reflux andheld for 14 hours. Mixture was concentrated in vacuo. Residue wastreated with acetonitrile (70 mL) and then concentrated in vacuo.Residue was crystallized from ethanol. Title compound was obtained aswhite solid in 77% yield. (M+H)⁺=230.1.

Methyl 2-(methylsulfonamido)benzoate. Methyl anthranilate (11.73 g, 77.6mmol) was dissolved in pyridine (25 mL, 309 mmol). Mixture was cooled to0° C. Methanesulfonyl chloride (6.60 mL, 85.3 mmol) was added to themixture drop-wise. Reaction mixture was warmed to room temperature andheld with stirring overnight. Mixture was diluted with ethyl acetate.Material was washed twice with water and three times with 1Nhydrochloric acid. Organic layer was dried (magnesium sulfate), filteredand then concentrated. Residue was triturated with 50% diethyl ether inhexanes. Solids were filtered off, washed with 50% diethylether-hexanes, washed with hexanes and then dried under high vacuum.Title compound was obtained as an off-white solid in 88% yield. MS m/e(M−H)⁻=227.9.

2,2-Dioxo-1-(2-trimethylsilanyl-ethoxymethyl)-2,3-dihydro-1H-2λ⁶-2,1-benzothiazin-4-one.In a dry round bottom flask under a blanket of nitrogen 60% sodiumhydride in mineral oil (1.05 g, 26 mmol) was washed with hexanes andthen suspended in N,N-dimethylformamide (50 mL). Mixture was cooled to0° C. A solution of methyl 2-(methylsulfonamido)benzoate (5.0 g, 22mmol) in 10 mL N,N-dimethylformamide was added to the mixture drop-wise.Reaction was held at 0° C. with stirring for 25 minutes.2-(Trimethylsilyl)ethoxymethyl chloride was added to the mixturedrop-wise. Reaction stirred for 2 hours slowly warming to ambienttemperature. Reaction was quenched with 1N hydrochloric acid. Materialwas extracted twice with ethyl acetate. Material was washed successivelywith water and brine. Organic phase was dried (magnesium sulfate),filtered and concentrated to dryness. Residue was dissolved inN,N-dimethylformamide (5 mL) and added drop-wise to a mixture of 60%sodium hydride in mineral oil (1.02 g, 26 mmol) that had been washedwith hexanes, suspended in N,N-dimethylformamide (50 mL) and cooled to0° C. Ice bath was removed and the mixture was allowed to warm to roomtemperature. Reaction was held at room temperature overnight withstirring. Reaction was quenched with 1N hydrochloric acid. Material wasextracted twice with ethyl acetate. Organic phase was washedsuccessively with water and brine. Organic phase was dried (magnesiumsulfate), filtered and concentrated to dryness. Silica gelchromatography (ethyl acetate-hexanes) afforded the title compound as awhite solid in 72% yield. MS m/e (M−H)⁻=326.0.

4-[2,2,4-Trioxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2,3,4-tetrahydro-2λ⁶-2,1-benzothiazin-3-yl]-piperidine-1-carboxylicacid tert-butyl ester. N-tert-Botoxycarbonyl-4-piperidinone (2.44 g, 12mmol) was dissolved in 1,2-dichloroethane (20 mL). Piperidine (1.2 mL,12 mmol) was added to the mixture. Reaction was heated to 50° C. andheld with stirring for 1.25 hours. Mixture was cooled to roomtemperature. A solution of2,2-Dioxo-1-(2-trimethylsilanyl-ethoxymethyl)-2,3-dihydro-1H-2λ⁶-2,1-benzothiazin-4-one(2.0 g, 6.1 mmol) in pyridine (5.0 mL, 62 mmol) was added to themixture. Reaction was held overnight at room temperature with stirring.Material was concentrated by roto-vap. Residue was dissolved in ethylacetate. Material was washed successively with three portions of 1Nhydrochloric acid and one portion of water. Organic phase was dried(magnesium sulfate), filtered and concentrated to dryness. Residue waspurified by silica gel chromatography (ethyl acetate-hexanes). Majorpeak was isolated and the fractions were concentrated to dryness.Residue was dissolved in methanol (40 mL). A catalytic amount of 10%palladium on carbon was added to the solution. Reaction vessel wasplaced on a Parr apparatus and charged with 60 psi of hydrogen gas.Reaction shook at room temperature overnight. Mixture was filtered overcelite. Fresh catalyst was added to the filtrate. Reaction vessel wasplaced on a Parr apparatus and charged with 60 psi of hydrogen gas.Reaction shook at room temperature for 7 hours. Mixture was filteredover celite and the filtrate was concentrated to dryness. Material waspurified by silica gel chromatography (ethyl acetate-hexanes). Majorpeak was isolated and the fractions were concentrated to dryness.Residue was dissolved in methanol (40 mL). Fresh catalyst was added tothe mixture. Reaction vessel was placed on a Parr apparatus and chargedwith 60 psi of hydrogen gas. Reaction shook at room temperatureovernight. Mixture was filtered over celite. Filtrate was concentratedto dryness. Silica gel chromatography (ethyl acetate-hexanes) affordedthe title compound as yellow oil in 43% yield. MS m/e (M−H)⁻=509.1.

4-[4-Hydroxy-2,2-dioxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2,3,4-tetrahydro-2λ⁶-2,1-benzothiazin-3-yl]-piperidine-1-carboxylicacid tert-butyl ester Title compound was obtained as yellow oil in 85%yield. Material was carried forward without purification.

3-Piperidin-4-yl-1H-2,1-benzothiazine 2,2-dioxide para-toluenesulfonate.4-[2,2,4-Trioxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2,3,4-tetrahydro-2λ⁶-2,1-benzothiazin-3-yl]-piperidine-1-carboxylicacid tert-butyl ester (865 mg, 1.7 mmol) was dissolved in methanol (25mL). Mixture was cooled to 0° C. Sodium borohydride (100 mg, 2.6 mmol)was added to the mixture in three portions. Reaction stirred at 0° C.for 3 hours. Mixture was concentrated by roto-vap. Residue was treatedwith 1N hydrochloric acid. Material was extracted twice with ethylacetate. Organic phase was dried (magnesium sulfate), filtered andconcentrated to dryness. Residue was dissolved in benzene (20 mL).p-Toluenesulfonic acid monohydrate (475 mg, 2.5 mmol) was added to themixture. Reaction was heated to reflux and held with stirring for 1hour. Mixture was cooled to room temperature. Solids were filtered off.The sticky solid was treated with hot isopropyl alcohol (10 mL). Mixturewas cooled to room temperature and allowed to stand overnight. Solidswere filtered off, washed with isopropyl alcohol and then dried underhigh vacuum. Title compound was obtained as tan solid in 65% yield. MSm/e (M+H)⁺=265.2.

2-(S)-(2-Acetoxymethyl-4-amino-5-bromo-3-methyl-benzyl)-succinic aciddiethyl ester. 2-(S)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinicacid diethyl ester (7.6 g, 21 mmol) was dissolved in acetic acid (100mL). Sodium acetate (4.2 g, 51 mmol) was added to the solution. Reactionvessel was placed in a cool water bath to control reaction exotherm.Bromine (1.1 mL, 22 mmol) was added to the mixture in one portion.Reaction stirred at ambient temperature for 10 minutes. Mixture waspoured into 1N aqueous sodium thiosulfate solution (400 mL). Materialwas extracted twice with ethyl acetate. Organic phase was washedsuccessively with water and brine. Organic was dried (magnesiumsulfate), filtered and concentrated in vacuo. Silica gel chromatography(ethyl acetate-hexanes) afforded the desired product in 77% yield as anamber oil. MS m/e (M−H)⁻=440.0, 442.0.

2-(S)-(4-Acetoxymethyl-7-bromo-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester. Isoamyl nitrite (2.3 mL, 17 mmol), was added drop-wise toan ice cold solution of2-(S)-(2-Acetoxymethyl-4-amino-5-bromo-3-methyl-benzyl)-succinic aciddiethyl ester (7.14 g, 16 mmol) in 5% acetic acid in toluene (280 mL).Mixture stirred at 0° C. for 40 minutes. Potassium acetate (4.00 g, 41mmol) was added to the mixture. Mixture was slowly warmed to roomtemperature. Reaction was stirred at room temperature for 14 hours.Mixture was washed twice with water and once with brine. Organic wasdried (magnesium sulfate) filtered and concentrated. Silica gelchromatography (ethyl acetate-hexanes) afforded the desired product in77% yield as an amber oil. MS m/e (M+H)⁺=455.0, 457.0.

(S)-dimethyl2-((7-bromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate.2-(S)-(2-Acetoxymethyl-4-amino-5-bromo-3-methyl-benzyl)-succinic aciddiethyl ester (2.78 g, 6.1 mmol) was converted to the title compound ina manner analogous to the preparation of2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester. Material was obtained as amber solid in 96% yield. MS m/e(M−H)⁻=383.0, 385.0.

(S)-dimethyl2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate.(S)-dimethyl2-((7-bromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (2.25 g,5.8 mmol) was dissolved in 2M thionyl chloride in dichloromethane (42mL, 84 mmol). Reaction stirred at room temperature for 2.0 hours.Mixture was concentrated. Residue was treated with toluene and thenconcentrated by roto-vap. Residue was dissolved in ethyl acetate.Mixture was washed twice with aqueous sodium bicarbonate. Organic wasdried (magnesium sulfate), filtered and concentrated in vacuo. Titlecompound was obtained as amber solid in 99% yield. MS m/e (M+H)⁺=404.9,403.0, 406.9.

[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. (S)-dimethyl2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (860 mg,2.1 mmol) was dissolved in acetonitrile (50 mL). Potassium carbonate(625 mg, 4.5 mmol) was added to the mixture followed by neopentylamine(800 μL, 6.78 mmol). Mixture was heated to reflux and held with stirringfor 1.5 hours. Mixture was cooled to room temperature. Mixture wasfiltered over celite. Filtrate was concentrated by roto-vap. Residue wasdissolved in a mixture of toluene (50 mL) and acetic acid (3 mL).Mixture was heated to reflux and held with stirring for 37 hours.Mixture concentrated by roto-vap. Silica gel chromatography (ethylacetate-hexanes) afforded the title compound as tan solid in 75% yield.MS m/e (M−H)⁻=420.0, 422.0.

[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid.[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (160 mg, 0.38 mmol) was dissolved in a mixture oftetrahydrofuran (5.0 mL) and methanol (5.0 mL). Water (5.0 mL) was addedto the mixture followed by lithium hydroxide monohydrate (41 mg, 0.98mmol). Mixture was heated to 50° C. and held with stirring for 5 hours.Mixture was cooled to room temperature. Organic solvents were removedfrom the mixture in vacuo. Remaining aqueous was diluted with water andthen made neutral with 1 mL of 1N hydrochloric acid. Material wasextracted twice with ethyl acetate. Organic phase was dried (magnesiumsulfate), filtered and concentrated to dryness. Title compound wasobtained as tan solid in quantitative yield. ¹H NMR (300 MHz, CDCl₃)δ=0.77 (s, 9 H) 2.31-2.60 (m, 3 H) 2.91 (dd, J=16.47, 8.42 Hz, 1 H)2.98-3.05 (m, 1 H) 3.09 (d, J=13.54 Hz, 1 H) 3.47 (d, J=13.91 Hz, 1 H)3.71-3.89 (m, 1 H) 4.39 (d, J=17.20 Hz, 1 H) 5.30 (d, J=17.20 Hz, 1 H)7.25 (s, 1 H) 8.00 (s, 1 H).

[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. (S)-dimethyl2-((7-bromo-4-chloromethyl)-1H-indazol-5-yl)methyl)succinate (860 mg,2.1 mmol) was dissolved in acetonitrile (50 mL). Potassium carbonate(625 mg, 4.5 mmol) was added to the mixture followed by neopentylamine(800 μL, 6.78 mmol). Mixture was heated to reflux and held with stirringfor 1.5 hours. Mixture was cooled to room temperature. Mixture wasfiltered over celite. Filtrate was concentrated by roto-vap. Residue wasdissolved in a mixture of toluene (50 mL) and acetic acid (3 mL).Mixture was heated to reflux and held with stirring for 37 hours.Mixture concentrated by roto-vap. Silica gel chromatography (ethylacetate-hexanes) afforded the title compound as tan solid in 75% yield.MS m/e (M−H)⁻=420.0, 422.0.

[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester.2-(S)-(4-chloromethyl-7-bromo-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester (325 mg, 0.81 mmol) was dissolved in acetonitrile (10 mL).Potassium carbonate (310 mg, 2.2 mmol) was added to the mixture with2,2,2-trifluoroethylamine (1.2 mL, 15 mmol). Mixture was heated at 60°C. and held with stirring for 15 hours. Mixture was cooled to roomtemperature. Mixture was filtered over celite. Filtrate was concentratedby roto-vap. Residue was dissolved in a mixture of toluene (10 mL) andacetic acid (600 μL). Mixture was heated to reflux and held withstirring for 22 hours. Mixture was concentrated by roto-vap. Residue wasdissolved in ethyl acetate. Material was washed successively with waterand aqueous sodium bicarbonate. Organic phase was dried (magnesiumsulfate), filtered and concentrated to dryness. Title compound wasobtained as amber residue in 74% yield. MS m/e (M−H)⁻=431.9, 433.9.

[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid.[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (250 mg, 0.58 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as light yellow solid in quantitativeyield. MS m/e (M−H)⁻=417.9, 419.9.

[4-Methyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester.[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (110 mg, 0.26 mmol) was dissolved inN,N-dimethylformamide (1.0 mL). Nitrogen gas was bubbled through themixture for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (6.0 mg,0.01 mmol) was added to the mixture followed by tetramethyltin (100 μL,0.72 mmol). Reaction vessel was flushed with nitrogen gas and thensealed. Reaction was subjected to microwave heating at 175° C. for 35minutes. Mixture was diluted with ethyl acetate. Material was washedsuccessively with water and brine. Silica gel chromatography (ethylacetate-hexanes) afforded the title compound as white solid in 83%yield. MS m/e (M+H)⁺=358.2.

[4-Methyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid.[4-Methyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (70 mg, 196 μmol) was dissolved in tetrahydrofuran(2.0 mL). Methanol (2.0 mL) was added to the mixture followed by water(2.0 mL) and then lithium hydroxide hydrate (20 mg, 477 μmol). Reactionwas warmed to 50° C. and held with stirring for 1.5 hours. Mixture wascooled to room temperature. Organic solvents were removed from themixture by roto-vap. Remaining aqueous was diluted with water and thenneutralized with 1N hydrochloric acid (500 μL). Mixture was extractedtwice with ethyl acetate. Organics were dried MgSO4, filtered and thenconcentrated to dryness. Title compound was obtained as white solid in95% yield. MS m/e (M−H)⁻=342.2.

2-(S)-(4-Acetoxymethyl-7-methyl-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester.2-(S)-(4-Acetoxymethyl-7-bromo-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester (350 mg, 0.77 mmol) and tetramethyltin (150 μL, 1.1 mmol)were reacted in a manner analogous to the preparation of[4-Methyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Title compound was obtained as pale yellow solid in68% yield. MS m/e (M−H)⁻=389.1.

(S)-dimethyl2-((7-methyl-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate.2-(S)-(2-Acetoxymethyl-4-amino-5-methyl-3-methyl-benzyl)-succinic aciddiethyl ester (230 mg, 0.59 mmol) was converted to the title compound ina manner analogous to the preparation of2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester. Material was obtained as off-white solid in 98% yield. MS m/e(M−H)⁻=319.2.

(S)-dimethyl2-((7-methyl-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate.(S)-dimethyl2-((7-methyl-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (180 mg,0.56 mmol) was dissolved in dichloromethane (4.0 mL). 2M Thionylchloride in dichloromethane (4.0 mL, 8.0 mmol) was added to the mixture.Reaction stirred at room temperature for 2.5 hours. Mixture wasconcentrated. Residue was treated with toluene and then concentrated byroto-vap. Residue was dissolved in dichloromethane and then concentratedto dryness. Title compound was obtained as amber solid in 99% yield. MSm/e (M+H)⁺=339.1.

[4-Methyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester.2-(S)-(4-chloromethyl-7-methyl-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester (190 mg, 0.56 mmol) and 2,2,2-trifluoroethylamine (45 μL,0.56 mmol) were reacted in a manner analogous to the preparation of[4-bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester. Title compound was obtained as amber residue in 76%yield. MS m/e (M+H)⁺=370.1.

[4-Methyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid.[4-Methyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (250 mg, 0.58 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as white solid in 97% yield. MS m/e(M−H)⁻=354.2.

[(S)-9-(2,2-Dimethyl-propyl)-4-isopropenyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester.[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (100 mg, 0.24 mmol) was dissolved in 2-propanol (1.0mL). Nitrogen gas was bubbled through the mixture for 5 minutes.Triethylamine (60 μL, 0.43 mmol) was added to the mixture followed by[1,1 ′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (19 mg,0.02 mmol) and potassium 2-propenyltrifluoroborate (41 mg, 0.28 mmol).Reaction vessel was flushed with nitrogen gas and then sealed. Reactionwas subjected to microwave heating at 150° C. for 30 minutes. Silica gelchromatography (ethyl acetate-hexanes) afforded the title compound asamber solid in 73% yield. MS m/e (M+H)⁺=384.4.

[(S)-9-(2,2-Dimethyl-propyl)-4-isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester.[(S)-9-(2,2-Dimethyl-propyl)-4-isopropenyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester (100 mg, 0.26 mmol) was dissolved in a mixture ofethyl acetate (5.0 mL) and methanol (5.0 mL). A catalytic amount of 10%palladium on carbon was added to the mixture. Reaction vessel was placedon a Parr apparatus and charged with 50 psi of hydrogen gas. Reactionshook at room temperature for 1 hour. Mixture was filtered and thefiltrate was concentrated to dryness. Title compound was obtained asbrown residue in 90% yield. MS m/e (M+H)⁺=386.3.

[(S)-9-(2,2-Dimethyl-propyl)-4-isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]aceticacid.[(S)-9-(2,2-Dimethyl-propyl)-4-isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester (90 mg, 0.23 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as white solid in 92% yield. MS m/e(M−H)⁻=370.3.

[4-Isopropenyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester.[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (400 mg, 0.92 mmol) and potassium2-propenyltrifluoroborate (165 mg, 1.1 mmol) were reacted in a manneranalogous to the preparation of[(S)-9-(2,2-Dimethyl-propyl)-4-isopropenyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester. Title compound was obtained as amber oil in 71%yield. MS m/e (M−H)⁻=394.1.

[4-Isopropyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester.[4-Isopropenyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (150 mg, 0.38 mmol) was reacted in a manner analogousto the preparation of[(S)-9-(2,2-Dimethyl-propyl)-4-isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester. Title compound was obtained as white solid in 73%yield. MS m/e (M+H)⁺=398.2.

[4-Isopropenyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid.[4-Isopropenyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (100 mg, 0.25 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as off-white solid in 98% yield. MSm/e (M−H)⁻=380.2.

[4-Isopropyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid.[4-Isopropyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (105 mg, 0.26 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as white solid in 99% yield. MS m/e(M−H)⁻=382.2.

[4-Ethyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester.[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (150 mg, 0.35 mmol) and tetraethyltin (200 μL, 1.0mmol) were reacted in a manner analogous to the preparation of[(S)-9-(2,2-Dimethyl-propyl)-4-methyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester. Title compound was obtained as clear colorless oil in28% yield. MS m/e (M+H)⁺=384.2.

[4-Ethyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-ylyaceticacid.[4-Ethyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (105 mg, 0.26 mmol) was reacted in a manner analogousto the preparation of [4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-acetic acid.Title compound was obtained as white solid in 73% yield. MS m/e(M−H)⁻=368.3.

((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-aceticacid methyl ester. (S)-dimethyl2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (630 mg,1.6 mmol) was dissolved in acetonitrile (5 mL). Potassium carbonate (560mg, 4.1 mmol) was added to the mixture followed by(aminomethyl)cyclopropane (700 μL, 8.1 mmol). Mixture was heated toreflux and held with stirring for 1.5 hours. Mixture was cooled to roomtemperature. Mixture was filtered. Filtrate was concentrated byroto-vap. Residue was dissolved in a mixture of toluene (10 mL) andacetic acid (1 mL). Mixture was heated to reflux and held with stirringfor 18 hours. Mixture was concentrated by roto-vap. Silica gelchromatography (ethyl acetate-hexanes) afforded the title compound astan solid in 64% yield. MS m/e (M+H)⁺=406.0, 408.0.

((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-aceticacid.((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-aceticacid methyl ester (290 mg, 0.71 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as yellow solid in 96% yield. MS m/e(M−H)⁻=390.0, 392.0.

[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester. (S)-dimethyl2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (400 mg,0.99 mmol) and 2-methoxyethylamine were reacted in a manner analogous tothe preparation of((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-aceticacid methyl ester. Title compound was obtained as tan solid in 66%yield. MS m/e (M−H)⁻=408.1, 410.0.

[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid.[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester (265 mg, 0.65 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as tan solid in 89% yield. MS m/e(M−H)⁻=394.1, 396.0.

N-(6-Fluoropyridin-2-yl)pivalamide. 6-fluoropyridin-2-amine (13.1 g, 117mmol) was dissolved in anhydrous pyridine (100 mL), and cooled to 0° C.followed by fast dropwise addition of trimethylacetyl chloride (15.9 mL,129 mmol) over 2 min. 5 min later, the resulting slurry was stirred overnight at room temperature. Partial of the solvent was removed on rotaryvacuum. The residue was partitioned between saturated ammonium chloride(200 mL) and EtOAc (200 mL). After separation, the organic layer waswashed with brine (50 mL), dried over MgSO₄, concentrated on rotaryvacuum, and purified on flash chromatography eluting with 25˜75%EtOAc/Hexanes (1400 mL) to afford the expected product as a white solid(21.4 g, 93% yield); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.29 (s, 9 H), 6.63(dd, J=8.06, 2.01 Hz, 1 H), 7.76 (q, J=8.14 Hz, 1 H), 7.85 (s, 1 H),8.09 (dd, J=8.06, 1.76 Hz, 1 H); Mass spec. 197.15 (MH⁺), Calc. forC₁₀H₁₃FN₂O196.1.

N-(6-Fluoro-3-formylpyridin-2-yl)pivalamide.N-(6-fluoropyridin-2-yl)pivalamide(1.67 g, 8.5 mmol) was dissolved inTHF (15 mL) at room temperature, and the colorless solution was cooledto −78° C., followed by dropwise addition of t-BuLi (10.3 mL, 1.7M inheptane, 17.4 mmol) under nitrogen gas over 10 min. The resulting yellowsolution was continued stirring at −78° C. for 3 hr, followed bydropwise addition of DMF (2.0 mL, 25.5 mmol) over 5 min. The lightyellow solution was stirred for additional 30 min at −78° C. Thus themixture was quenched with saturated NH₄Cl (30 mL), partitioned betweenH₂O/EtOAc (100 mL/100 mL). After separation, the organic phase waswashed with brine (30 mL), dried over MgSO₄, concentrated on rotaryvacuum, and purified on flash chromatography eluting with 25˜50%EtOAc/hexanes (1400 mL) to afford an expected product, as a white solids(343 mg, 18% yield), plus the recovered starting material (622 mg); ¹HNMR (400 MHz, CDCl₃) δ ppm 1.23-1.30 (s, 9 H), 8.12 (s, 1 H), 8.18-8.27(m, 2 H), 10.13 (s, 1 H); Mass spec. 225.13 (MH⁺), Calc. forC₁₁H₁₃FN₂O₂224.1.

tert-butyl4-(1-(6-Fluoro-2-pivalamidopyridin-3-yl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate.To diisopropylamine (0.47 mL, 3.35 mmol) in anhydrous THF (10 mL) wasdropwise added n-BuLi (2.5 M in heptane, 1.4 mL, 3.48 mmol) at −78° C.under N₂ over 10 min. 15 min later, tert-butyl4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (861 mg, 3.35 mmol) inTHF (10 mL) was dropwise added at −78° C. over 10 min. The resultingmixture was stirred for 45 min. At the same time,N-(6-fluoro-3-formylpyridin-2-yl)pivalamide (500 mg, 2.23 mmol), wasdissolved in anhydrous THF (10 mL) in another oven dried round bottomflask, and dropwise added to NaH (60% in mineral oil, 93.7 mg, 2.34mmol) in THF (10 mL) at ° C. The resulting yellow suspension was stirredat 0° C. under N₂ for 1 hr, which then was transferred to the aboveanion solution at −78° C. through a syringe over 10 min. The resultingsuspension was continued stirring at −78° C. for 1 hr. Quenched withsaturated NH₄Cl (50 mL), extracted with EtOAc (2×100 mL). The combinedorganic layers were washed with brine (30 mL), dried on MgSO₄,concentrated on rotary vacuum and purified on flash chromatographycolumn eluting with 20˜75% EtOAc/hexanes (1000 mL), 75˜100%EtOAc/hexanes (600 mL) to afford the expected inseparable stereo isomermixture, as a white product (536 mg, 50% yield), plus recovered startingmaterial, N-(6-fluoro-3-formylpyridin-2-yl)pivalamide (140 mg); Massspec. 482.23 (MH⁺), Calc. for C₂₄H₃₆FN₃O₆ 481.26.

7-Fluoro-3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one hydrochloride.The mixture of tert-butyl4-(1-(6-fluoro-2-pivalamidopyridin-3-yl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate(238 mg, 0.494 mmol), and concentrated HCl (1 mL) in MeOH (1 mL) and H₂O(1 mL) was refluxed under N₂ over night. The solvents were removed onrotary vacuum, the residue, as a yellow solid, was triturated with coldEtOH (2×3 mL), filtrated and dried under vacuum to afford an expectedproduct, a yellow solid (139 mg, 99% yield); ¹H NMR (400 MHz, MeOD) δppm 1.27 (s, 1 H), 1.83-1.95 (m, 2 H), 2.13 (d, J=14.10 Hz, 2H),3.06-3.18 (m, 3 H), 3.49 (d, J=12.84 Hz, 2 H), 6.47 (d, J=8.81 Hz, 1H), 7.69 (s, 1 H), 7.85 (d, J=9.06 Hz, 1 H); Mass spec. 248.13 (MH⁺),Calc. for C₁₃H₁₄FN₃O 247.11.

2-Bromo-5-fluorobenzenamine. To a solution of1-bromo-4-fluoro-2-nitrobenzene (5.0 g, 22.7 mmol) in HOAc/EtOH (20mL/20 mL) was added iron powder in one portion at room temperature. Themixture was bubbled with N₂ for 5 min, and then refluxed for 2 hrs.Partial of the solvents were removed on rotary vacuum, then the residuewas partitioned between aqueous NaOH (10N, 200 mL) and Et₂O (200 mL).After separation, the organic phase was washed with H₂O (50 mL), brine(50 mL), dried on MgSO₄, and concentrated on rotary vacuum to afford theexpected product, as an light tan oil (quantitative yield), which waspure enough to be used in next step without further purification; ¹H NMR(400 MHz, CDCl₃) δ ppm 4.15 (s, 1 H), 6.34 (td, J=8.44, 2.77 Hz, 1 H),6.46 (dd, J=10.20, 2.90 Hz, 1 H), 7.31 (dd, J=8.81, 5.79 Hz, 1 H); Massspec. 189.94 (MH⁺), Calc. for C₆H₅BrFN 188.96.

N-(2-Bromo-5-fluorophenyl)pivalamide. Trimethylacetyl chloride (4.2 mL,34.1 mL) was fast dropwise added to a solution of2-bromo-5-fluorobenzenamine (4.31 g, 22.7 mmol) in CH₂Cl₂ (50 mL) atroom temperature, followed by the addition of DIEA (7.9 mL, 45.4 mmol).The resulting mixture was stirred at room temperature for 2 hrs, andthen partitioned between HCl (1N, 200 mL) and EtOAc(250 mL). Afterseparation, the organic phase was washed with brine (50 mL), dried onMgSO₄, concentrated on rotary vacuum, and purified on flashchromatography eluting with 20˜40% EtOAc/hexanes (1200 mL) to afford theexpected product, as a colorless oil (6.07 g, 98% yield); ¹H NMR (400MHz, CDCl₃) δ ppm 1.33 (s, 9 H), 6.69 (ddd, J=8.81, 7.55, 3.02 Hz, 1 H),7.45 (dd, J=8.81, 5.79 Hz, 1 H), 8.04 (s, 1 H), 8.28 (dd, J=11.08, 3.02Hz, 1 H); Mass spec. 274.04 (MH⁺), Calc. for C₁₁H₁₃BrFNO 273.02.

N-(5-Fluoro-2-formylphenyl)pivalamide.N-(2-bromo-5-fluorophenyl)pivalamide (2.4 g, 8.75 mmol)) was dissolvedin THF (30 mL) at room temperature, and the colorless solution wascooled to −78° C., followed by fast dropwise addition of t-BuLi (10.3mL, 1.7M in heptane, 17.4 mmol) under N₂ over 10 min. The resultingyellow solution was continued stirring at −78° C. for 1 hr, followed bydropwise addition of DMF (2.7 mL, 35.0 mmol) over 5 min. The lightyellow solution was stirred for additional 30 min at −78° C. Thus themixture was quenched with saturated NH₄Cl (30 mL), extracted with Et₂O(2×150 mL). The combined organic phase was washed with brine (30 mL),dried over MgSO₄, concentrated on rotary vacuum, and purified on flashchromatography eluting with 25˜50% EtOAc/hexanes (1400 mL) to afford anexpected product, as a white solids (1.03 g, 53% yield); ¹H NMR (400MHz, CDCl₃) δ ppm 1.30 (s, 9 H), 6.80-6.86 (m, 1 H), 7.63 (dd, J=8.56,6.04 Hz, 1 H), 8.53 (dd, J=12.21, 2.39 Hz, 1 H), 9.83 (s, 1 H), 11.54(s, 1 H); Mass spec. 224.16(MH⁺), Calc. for C₁₂H₁₄FNO₂ 223.1.

tert-butyl4-(1-(4-Fluoro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate.The procedure was the same as the synthesis of t-butyl4-(1-(6-fluoro-2-pivalamidopyridin-3-yl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate.The reaction gave an inseparable stereo isomer mixture, tert-butyl4-(1-(4-fluoro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate.The crude compound was used directly in the next step without furtherpurification. Mass spec. 481.25(MH⁺), Calc. for C₂₅H₃₇FN₂O₆ 480.26.

7-Fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride. Theprocedure was the same as the synthesis of7-fluoro-3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one, and gave theexpected product, 7-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride, as a white solid at the 41% yield after two steps; ¹H NMR(400 MHz, MeOD) δ ppm 1.84-1.96 (m, 2 H), 2.15 (d, J=14.10 Hz, 2 H),3.07-3.16 (m, 3 H), 3.50 (d, J=12.84 Hz, 2 H), 6.98-7.05 (m, 2 H), 7.69(dd, J=8.56, 5.79 Hz, 1 H), 7.78 (s, 1 H); Mass spec. 247.12 (MH⁺),Calc. for C₁₄H₁₅FN₂O 246.12.

(2-Amino-4-chlorophenyl)methanol. Methyl 2-amino-4-chlorobenzoate (1.5g, 8.08 mmol) in THF (15 mL) was dropwise added to the suspension of LAH(429 mg, 11.3 mmol) in THF (10 mL) under N₂ at 0° C. over 10 min. Theresulting mixture was stirred at room temperature for 2 hrs, then thereaction was quenched at 0° C. with saturated Na₂SO₄ (50 mL), extractedwith Et₂O (2×70 mL). The combined organic solutions were washed withbrine (30 mL), dried on MgSO₄, and concentrated on rotary vacuum toafford the expected product as a white solid (874 mg, 69% yield); ¹H NMR(400 MHz, MeOD) δ ppm 4.50 (s, 2 H), 6.58 (dd, J=8.06, 2.01 Hz, 1 H),6.70 (d, J=2.01 Hz, 1 H), 7.01 (d, J=8.06 Hz, 1 H); Mass spec. 157.06(MH⁺), Calc. for C₇H₈ClNO 157.03.

N-(5-Chloro-2-(hydroxymethyl)phenyl)pivalamide. Trimethylacetyl chloride(0.72 mL, 5.82 mmol) was fast dropwise added to(2-amino-4-chlorophenyl)methanol (874 mg, 5.55 mmol) in CH₂Cl₂ (20 mL)and THF (6 mL) at 0° C., and followed by the addition of DIEA (2.41 mL,13.9 mmol). The resulting mixture was stirred for 30 min. Then themixture was partitioned between saturated NaHCO₃ (50 mL) and CH₂Cl₂ (100mL). After separation, the organic phase was washed with brine (30 mL),dried on MgSO₄, and concentrated on rotary vacuum to afford the expectedcrude product (1.34, 100% yield), which was pure enough to be used innext step. Mass spec. 242.08 (MH⁺), Calc. for C₁₂H₁₆ClNO₂ 241.09.

N-(5-Chloro-2-formylphenyl)pivalamide. Pyridiniumchlorochromate (1.67 g,7.77 mmol) was added to N-(5-chloro-2-(hydroxymethyl)phenyl)pivalamide(1.34 g, 5.55 mmol) in CH₂Cl₂ (100 mL) at 0° C. 5 min later, thereaction mixture was stirred at room temperature for 3 hrs. Then it waspassed through a thin silica gel pad with CH₂Cl₂ (100 mL), concentratedon rotary vacuum and purified on flash chromatography eluting with20˜40% EtOAc/hexanes (800 mL) to afford the expected product as a whitesolid (937 mg, 70% yield). ¹H NMR (400 MHz, CHLOROFORM-D) δ ppm1.28-1.34 (s, 9 H), 7.15 (dd, J=8.31, 2.01 Hz, 1 H), 7.53-7.59 (m, 1 H),8.87 (d, J=2.01 Hz, 1 H), 9.84-9.88 (m, 1 H), 11.42 (s, 1 H); Mass spec.240.07 (MH⁺), Calc. for C₁₂H₁₄ClNO₂ 239.07.

tert-butyl4-(1-(4-Chloro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate.The reaction procedure was the same as the synthesis of tert-butyl4-(1-(6-fluoro-2-pivalamidopyridin-3-yl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate.The reaction afforded tert-butyl4-(1-(4-chloro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylatestereoisomer mixture as a white solid (73% total yield) afterpurification on flash chromatography, which was directly used in nextstep. Mass spec. 497.19 (MH⁺), Calc. for C₂₅H₃₇ClN₂O₆ 496.23.

7-Chloro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride. Theprocedure was the same as the synthesis of7-fluoro-3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one. After reaction,partial of the solvent was removed on rotary vacuum, the expectedproduct came out from the solution, filtration and washing with EtOH togave a white solid (71% yield). ¹H NMR (400 MHz, MeOD) δ ppm 1.83-1.94(m, 2 H), 2.14 (d, J=12.84 Hz, 2 H), 3.07-3.19 (m, 3 H), 3.48 (s, 1 H),3.51 (d, J=1 H), 7.18-7.23 (m, J=6.30, 4.34, 2.20, 2.01 Hz, 1 H),7.30-7.35 (m, 1 H), 7.59-7.65 (m, 1 H), 7.74-7.78 (m, 1 H); Mass spec.263.07 (MH⁺), Calc. for C₁₄H₁₅ClN₂O 262.09.

(2-Amino-4,5-difluorophenyl)methanol. 2-Amino-4,5-difluorobenzoic acid(5.37 g, 31.0 mmol) in THF (50 mL) was dropwise added to the suspensionon LAH (1.65 g, 43.5 mmol) in THF (15 mL) at room temperature under N₂over 10 min. The resulting suspension was stirred at room temperaturefor 1 hr. Then the mixture was cooled down to 0° C., quenched withsaturated Na₂SO₄ (100 mL), and extracted with Et₂O (2×100 mL), thecombined organic layers were washed with brine (60 mL), dried overMgSO₄, and concentrated on rotary vacuum to afford the expected crudeproduct as a brown solid, which was pure enough to be used in next stepwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 4.07 (s, 1H), 4.56 (s, 2 H), 6.46 (dd, J=11.71, 6.92 Hz, 1 H), 6.87 (dd, J=10.58,8.56 Hz, 1 H); Mass spec. 160.04 (MH⁺), Calc. for C₇H₇F₂NO 159.05.

N-(4,5-Difluoro-2-(hydroxymethyl)phenyl)pivalamide. Trimethylacetylchloride (4.01 mL, 32.55 mmol) was added to the solution of the crude(2-amino-4,5-difluorophenyl)methanol in CH₂Cl₂/THF (50 mL/10 mL) at 0°C., followed by the addition of DIEA (10.8 mL, 62 mmol). The resultingmixture was stirred for 30 min, and then partitioned between saturatedNaHCO₃(100 mL) and CH₂Cl₂ (150 mL). After separation, the organic phasewas washed with brine (40 mL), dried over MgSO₄, and concentrated onrotary vacuum to afford the expected product, which was pure enough tobe used in next step without further purification; ¹H NMR (400 MHz,CDCl₃) δ ppm 1.28 (s, 9 H), 4.62 (s, 2 H), 6.94 (dd, J=10.20, 8.44 Hz, 1H), 8.08 (dd, J=12.72, 7.68 Hz, 1 H), 9.04 (s, 1 H); Mass spec. 244.11(MH⁺), Calc. for C₁₂H₁₅F₂NO₂ 243.11.

N-(4,5-Difluoro-2-formylphenyl)pivalamide. Pyridiniumchlorochromate(9.36 g, 43.4 mmol) was added to the solution of the crudeN-(4,5-difluoro-2-(hydroxymethyl)phenyl)pivalamide in CH₂Cl₂ (150 mL) atrt. The yellow solution turned into dark brown in 10 min, and themixture was continued stirring for 3 hr, and then passed through a thinsilica gel pad with CH₂Cl₂ (2×50 mL). The combined organic solution wasconcentrated on rotary vacuum, and purified on flash chromatographyeluting with 20˜60% EtOAc/hexanes (1300 mL) to afford the expectedproduct as a brown solid (1.91 g, 26% yield after three step); ¹H NMR(400 MHz, CDCl₃) δ ppm 1.29 (s, 9 H), 7.42-7.48 (m, 1 H), 8.75 (dd,J=13.35, 7.30 Hz, 1 H), 9.77-9.80 (m, 1 H), 11.40 (s, 1 H); Mass spec.242.08 (MH⁺), Calc. for C₁₂H₁₃F₂NO₂ 241.09.

tert-butyl4-(1-(4,5-Difluoro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate.The reaction procedure was the same as the synthesis of tert-butyl4-(1-(6-fluoro-2-pivalamidopyridin-3-yl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate.The reaction afforded an inseparable tert-butyl4-(1-(4,5-difluoro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylatestereo isomer mixture, as a white solid (70% total yield) afterpurification on flash chromatography, which was used in next step. Massspec. 499.19 (MH⁺), Calc. for C₂₅H₃₆F₂N₂O₆ 498.25.

6,7-Difluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride. Theprocedure was the same as the synthesis of7-fluoro-3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one. After reaction,partial of the solvent was removed on rotary vacuum, the expectedproduct came out from the solution, filtration and washing with ethanolto gave a white solid (77% yield); ¹H NMR (400 MHz, MeOD), δ ppm1.81-1.93 (m, 2 H), 2.13 (d, J=2.01 Hz, 2 H), 3.07-3.19 (m, 4 H), 3.50(d, J=14.35 Hz, 1 H), 7.16-7.23 (m, 1 H), 7.55-7.62 (m, 1 H), 7.71-7.77(m, 1 H); Mass spec. 265.07 (MH⁺), Calc. for C₁₄H₁₄F₂N₂O 264.11.

Methyl 3-chloro-2-nitrobenzoate. To 3-chloro-2-nitrobenzoic acid (3.15g, 15.6 mmol) in methanol/acetonitrile (20 mL/20 mL) was dropwise addedTMSCHN₂ (2N in hexanes, 11.7 mL, and 23.4 mmol) at 0° C. under N₂ over10 min until the yellow color persist. The mixture was continuedstirring for 20 min, followed by dropwise addition of HOAc until theyellow color disappeared to kill excessive TMSCHN₂. Partial of thesolvent was removed on rotary vacuum, the product came out solution as alight yellow solid, which was filtered and washed with Et₂O (2×2 mL) toafford the expected product as a white solid (2.5 g, 74% yield); ¹H NMR(400 MHz, CDCl₃) δ ppm 3.91 (s, 3 H), 7.51 (t, J=8.06 Hz, 1 H), 7.70(dd, J=8.06, 1.26 Hz, 1 H), 7.97 (dd, J=7.81, 1.26 Hz, 1 H); Mass spec.216.02 (MH⁺), Calc. for C₈H₆ClNO₄ 215.00.

Methyl 2-amino-3-chlorobenzoate. Iron powder (1.94 g, 34.8 mmol) wasadded to the solution of methyl 3-chloro-2-nitrobenzoate (2.5 g, 11.6mmol) in EtOH/HOAc (100 mL/100 mL) at room temperature, and then thesuspension was refluxed under N₂ for 2 hrs. After cooling down to roomtemperature, partial of the solvents was removed on rotary vacuum, theresulting residue was partitioned between H₂O/EtOAc (200 mL/300 mL). Theseparated organic phase was washed with aqueous NaOH (1N, 50 mL), brine(50 mL), dried over MgSO₄, and concentrated on rotary vacuum to affordthe expected product as a tan oil (1.7 g, 79% yield) which became waxtype solid standing on bench. The crude product was pure enough to beused in next step without further purification; ¹H NMR (400 MHz, CDCl₃)δ ppm 3.86 (s, 3 H), 6.25 (s, 2 H), 6.57 (t, J=7.93 Hz, 1 H), 7.39 (dd,J=7.81, 1.51 Hz, 1 H), 7.79 (dd, J=8.06, 1.51 Hz, 1 H); Mass spec.185.95 (MH⁺), Calc. for C₈H₈ClNO₂ 185.02.

(2-Amino-3-chlorophenyl)methanol. A solution of methyl2-amino-3-chlorobenzoate (1.7 g, 9.16 mmol) in THF (40 mL) was dropwiseadded to a suspension of the LAH (521 mg, 13.7 mmol) in THF (15 mL) atroom temperature over 10 min under N₂, and stirred for 2 hrs. Thereaction was carefully quenched with saturated Na₂SO₄ (10 mL) at 0° C.,extracted with Et₂O (2×50 mL). The combined organic layers were washeswith brine (30 mL), dried on MgSO₄, and concentrated on rotary vacuum toafford the expected product as a yellow solid (1.08 g, 75%), which waspure enough to be used in the next step without further purification; ¹HNMR (400 MHz, CDCl₃), δ ppm 1.65 (s, 1 H), 4.59-4.70 (m, 4 H), 6.60-6.65(m, 1 H), 6.96 (dd, J=7.55, 1.26 Hz, 1 H), 7.19-7.25 (m, 1 H); Massspec. 158.02 (MH⁺), Calc. for C₇H₈ClNO₂ 157.03.

N-(2-Chloro-6-(hydroxymethyl)phenyl)pivalamide. To the crude(2-amino-3-chlorophenyl)methanol (1.08 g, 6.88 mmol) in CH₂Cl₂(15 mL)was fast dropwise added trimethylacetyl chloride (0.89 mL, 7.23 mmol),followed by DIEA (2.4 mL, 13.8 mmol) at 0° C. 5 min later, the reactionmixture was stirred at room temperature for 1 hr. Normal aqueous work-upto afford the expected product as a white solid (1.58 g, 95% yield),which was pure enough to be used in next step; ¹H NMR (400 MHz, CDCl₃) δppm 1.30 (s, 9 H), 3.35 (s, 2 H), 4.36 (d, J=6.29 Hz, 1 H), 7.06-7.22(m, J=7.81, 7.81 Hz, 1 H), 7.29-7.33 (m, 2 H), 7.58 (s, 1 H); Mass spec.242.08 (MH⁺), Calc. for C₁₂H₁₆ClNO₂ 241.09.

N-(5-Chloro-2-formylphenyl)pivalamide. Pyridinium chlorochromate (1.19g, 5.5 mmol) was added to a solution ofN-(2-chloro-6-(hydroxymethyl)phenyl)pivalamide (884 mg, 3.67 mmol) inCH₂Cl₂ (100 mL) at 0° C. 5 min later the mixture was allowed stirring atroom temperature for 3 hrs. The reaction mixture was passed through athin pad layer of silica gel with CH₂Cl₂(2×100 mL), concentrated onrotary vacuo, and purified on a flash chromatography column eluting with20˜50% EtOAc/hexanes (1000 mL) to afford the expected product as a whitesolid (414 mg, 47% yield); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37 (s, 9 H),7.30 (t, J=7.81 Hz, 1 H), 7.64 (dd, J=7.93, 1.39 Hz, 1 H), 7.77 (dd,J=7.55, 1.51 Hz, 1 H), 8.25 (s, 1 H), 9.84 (s, 1 H); Mass spec. 240.08(MH⁺), Calc. for C₁₂H₁₄ClNO₂ 239.07.

tert-butyl4-(1-(3-Chloro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate.The reaction procedure was the same as the synthesis of tert-butyl4-(1-(6-fluoro-2-pivalamidopyridin-3-yl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate.The reaction afforded an inseparable stereo isomer mixture of tert-butyl4-(1-(3-chloro-2-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate,as a white solid (56% yield) after purification on flash chromatography.Mass spec. 497.22(MH⁺), Calc. for C₂₅H₃₇ClN₂O₆ 496.23.

8-Chloro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride. Theprocedure was the same as the synthesis of7-fluoro-3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one. After reaction,partial of the solvent was removed on rotary vacuum, the expectedproduct came out as a solid from the solution, filtration and washingwith ethanol to gave the expected product,8-chloro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride, a whitesolid (71% yield); ¹H NMR (400 MHz, MeOD) δ ppm 1.85-1.96(m, 2H), 2.17(d, J=13.85 Hz, 2 H), 3.10-3.20 (m, 4 H), 3.46-3.54 (m, 2H), 7.23(t,J=7.81 Hz, 1 H), 7.59-7.64 (m, 2 H), 7.81 (s, 1 H); Mass spec. 263.08(MH⁺), Calc. for C₁₄H₁₅ClN₂O 262.09.

Methyl 2-fluoro-6-nitrobenzoate. To 2-fluoro-6-nitrobenzoic acid (712mg, 3.85 mmol) in methanol/acetonitrile (10 mL/10 mL) was dropwise addedTMSCHN₂ at 0° C. under N₂ until yellow color persistent, and stirredadditional 30 min. Then the reaction was quenched with HOAcat 0° C.until the yellow color disappears. Partial of the solvent was removed orotary vacuum, the residue was dissolved in small amount of EtOAc,purified on flash chromatography eluting with 30˜50% EtOAc/hexanes (600mL) to afford the expected product, methyl 2-fluoro-6-nitrobenzoate,(716 mg, 94% yield) which was used in step-2; ¹H NMR (400 MHz, CDCl₃) δppm 3.96 (s, 3 H), 7.40-7.48 (m, 1 H), 7.58 (td, J=8.31, 5.54 Hz, 1 H),7.94 (d, J=8.31 Hz, 1 H); Mass spec. 200.05 (MH⁺), Calc. for C₈H₆FNO₄199.03.

Methyl 2-amino-6-fluorobenzoate. Methyl 2-fluoro-6-nitrobenzoate (715mg, 3.59 mmol) was dissolved in EtOH/HOAc/(10 mL/10 mL), followed byaddition of iron powder (602 mg, 10.8 mmol) at room temperature. Theresulting mixture was refluxed under N₂ for 2 hrs. After cooling down toroom temperature, the brown suspension was partitioned between H₂O (30mL) and Et₂O (100 mL). After separation, the aqueous solution wasextracted with Et₂O (50 mL). The combined organic layers were washedwith 1N NaOH (3×50 mL), brine (50 mL), dried on MgSO₄, and concentratedon rotary vacuum to afford the expected product, methyl2-amino-6-fluorobenzoate, an colorless oil which became wax-type solidon standing. The crude compound was pure enough to be used in next stepwithout further purification; ¹H NMR (400 MHz, CDCl₃) δ ppm 3.89 (s, 3H), 5.67 (s, 2 H), 6.34 (ddd, J=11.58, 8.06, 1.01 Hz, 1 H), 6.41 (d,J=8.31 Hz, 1 H), 7.13 (td, J=8.18, 5.79 Hz, 1 H); Mass spec. 170.06(MH⁺), Calc. for C₈H₈FNO₂ 169.05.

(2-Amino-6-fluorophenyl)methanol. Methyl 2-amino-6-fluorobenzoate, acrude compound obtained in the last step, dissolved in THF (15 mL) wasdropwise added to the suspension of LAH (204 mg, 5.39 mmol) at roomtemperature over 5 minutes. The mixture was stirred for 1 hr, thencooled down to 0° C., quenched with saturated Na₂SO₄ and extracted withEt₂O (2×50 mL). The combined organic layers were washed with brine (30mL). dried on MgSO₄, concentrated on rotary vacuum to give an expectedcrude product, (2-amino-6-fluorophenyl)methanol, as a brown solid (268.1mg), which was pure enough to be used in the next step without furtherpurification; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.64 (s, 1 H), 4.30 (s, 2H), 4.75 (s, 2 H), 6.39-6.47 (m, 2 H), 7.02 (td, J=8.18, 6.30 Hz, 1 H);Mass spec. 142.08 (MH⁺), Calc. for C₇H₈FNO 141.06.

N-(3-Fluoro-2-(hydroxymethyl)phenyl)pivalamide. Trimethylacetyl chloride(0.25 mL, 1.99 mmol) was added to a solution of(2-amino-6-fluorophenyl)methanol (268 mg, 1.90 mmol) in CH₂Cl₂ (10 mL)at 0° C., followed by the addition of DIEA (1.0 mL, 5.7 mmol). Themixture was stirred for 1 hr, followed by normal aqueous work-up toafford the expected crude product,N-(3-fluoro-2-(hydroxymethyl)phenyl)pivalamide, as a colorless oil (415mg, 97% yield), which was used directly in the next step; ¹H NMR (400MHz, CDCl₃) δ ppm 1.29 (s, 9 H), 2.64 (s, 1 H), 4.78 (d, J=4.78 Hz, 2H), 6.75-6.84 (m, 1 H), 7.23 (td, J=8.62, 5.92 Hz, H), 7.86 (d, J=8.31Hz, 1 H), 8.97 (s, 1 H); Mass spec. 226.11 (MH⁺), Calc. for C₁₂H₁₆FNO₂225.12.

N-(3-Fluoro-2-formylphenyl)pivalamide. Pyridinium chlorochromate (596mg, 2.76 mmol) was added to a solution of N-(3-fluoro-2-(hydroxymethyl)phenyl)pivalamide (415 mg, 1.84 mmol) in CH₂Cl₂ (50 mL) at 0° C. 5 minlater the mixture was allowed stirring at room temperature for 3 hrs.The reaction mixture was passed through a thin pad layer of silica gelwith CH₂Cl₂(2×50 mL), concentrated on rotary vacuum, and purified on aflash chromatography column eluting with 20˜50% EtOAc/hexanes (600 mL)to afford the expected product, N-(3-fluoro-2-formylphenyl)pivalamide,as a white solid (396 mg, 46% yield after five steps); ¹H NMR (400 MHz,CDCl₃) δ ppm 1.33 (s, 9 H), 6.76-6.83 (m, 1 H), 7.54 (td, J=8.44, 6.55Hz, 1 H), 8.56 (d, J=8.56 Hz, 1 H), 10.38 (s, 1 H), 11.57 (s, 1 H); Massspec. 224.11 (MH⁺), Calc. for C₁₂H₁₄FNO₂ 223.1.

tert-butyl4-(1-(2-Fluoro-6-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate.The reaction procedure was the same as the synthesis of tert-butyl4-(1-(6-fluoro-2-pivalamidopyridin-3-yl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate.The reaction afforded a stereo isomer mixture of the expected crudeproduct, tert-butyl4-(1-(2-fluoro-6-pivalamidophenyl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate,as a colorless oil which was used directly in the next step withoutfurther purification. Mass spec. 481.24 (MH⁺), Calc. for C₂₅H₃₇FN₂O₆480.26.

5-Fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride. Theprocedure was the same as the synthesis of7-fluoro-3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one. After reaction,partial of the solvent was removed on rotary vacuum, the expectedproduct came out as a solid from the solution, filtration and washingwith ethyl ethanol to gave the expected product,5-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride, a whitesolid (43% yield after two steps); ¹H NMR (400 MHz, MeOD) δ ppm1.85-1.96 (m, 2 H), 2.16 (d, J=14.10 Hz, 2 H), 3.16 (td, J=13.03, 2.90Hz, 3 H), 3.51 (dd, J=10.58, 2.01 Hz, 2 H), 4.55 (s, 1 H), 6.94-6.99 (m,1 H), 7.13 (d, J=8.31 Hz, 1 H), 7.48 (td, J=8.31, 5.79 Hz, 1 H), 7.90(s, 1 H); Mass spec. 247.11 (MH⁺), Calc. for C₁₄H₁₅FN₂O 246.12.

2-(Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzylidene)-succinicacid diethyl ester. Nitrogen gas was bubbled through a solution ofacetic acid 3-tert-butoxycarbonylamino-6-iodo-2-methyl-benzyl ester(3.85 g, 9.5 mmol), itaconic acid diethyl ester (2.2 mL, 12 mmol),tetrabutylammonium chloride (3.4 g, 12 mmol), and triethylamine (4.0 mL,29 mmol) in N,N-dimethylformamide (25 mL) for 5 minutes. Palladium (II)acetate (0.32 g, 1.4 mmol) was added. Mixture was heated at 100° C. for45 minutes. Mixture was cooled to room temperature then diluted withdiethyl ether (100 ml). Mixture was washed successively with water (3×50mL), and brine (25 mL). Organic was dried (MgSO₄), filtered andconcentrated in vacuo. Silica gel purification yielded the desiredproduct in 99% yield as an amber oil. ¹H NMR (300 MHz, CDCl₃): δ=8.0 (s,1H), 7.78 (d, J=8.4, 1H), 7.08 (d, J=8.4, 1H), 6.32 (s, 1H), 5.11 (s,2H), 4.27 (q, J=7.3, 2H), 4.11 (q, J=7.1, 2H), 3.30 (s, 2 H), 2.24 (s,3H), 2.04 (s, 3H), 1.55 (s, 3H), 1.51 (s, 9H), 1.32 (t, J=7.1, 3H), 1.23(t, J=7.3, 3H). MS m/e (M−H)⁻=462.0.

2-(S)-(Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester.2-(S)-(Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzylidene)-succinicacid diethyl ester (4.4 g, 9.5 mmol) and(−)-1,2-bis((2R,5R)-diethylphospholano)benzene(cyclooctadiene)rhodium(I) trifluoromethane sulfonate (100 mg) was dissolved in ethanol (80mL). Mixture was placed on a Parr hydrogenation apparatus. Reactionvessel was charged with 60 psi of hydrogen gas. Reaction mixture wasallowed to shake at room temperature for 18 hours. Reaction mixture wasconcentrated in vacuo. Residue was passed through a plug of silica geleluting 80% ethyl acetate-hexanes (250 mL). Filtrate was concentrated invacuo to afford the desired product in 97% yield as an amber oil. ¹H NMR(300 MHz, CDCl₃): δ=7.62 (d, J=8.1, 1H), 7.01 (d, J=8.4, 1H), 6.20 (s,1H), 5.20 (m, 2H), 4.09 (m, 4H), 3.14 (m, 1H), 2.69 (m, 2H), 2.38 (dd,J1=16.8, J2=4.8, 1H), 2.23 (s, 3H), 2.07 (s, 3H), 1.56 (3, 3H), 1.50 (s,9H), 1.22 (m, 6H). MS m/e (M−H)⁻=464.0.

2-(S)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethylester. Trifluoroacetic acid (10 mL) was added to a solution of2-(S)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester (4.6 g, 9.9 mmol) in dichloromethane (40 mL).Reaction mixture was stirred at room temperature for 1.5 hours. Mixturewas concentrated in vacuo. Residue was dissolved in dichloromethane (75mL) and washed successively with saturated aqueous sodium bicarbonate(2×50 mL) and brine (30 mL). Organic was dried (magnesium sulfate),filtered and concentrated in vacuo to yield the desired product in 99%yield as an amber oil. ¹H NMR (300 MHz, CDCl₃): δ=6.85 (d, J=8.1, 1H),6.67 (d, J=8.4, 1H), 5.18 (m, 2H), 4.09 (m, 4H), 3.09 (dd, J1=6.2,J2=13.9, 1 H), 2.96 (m, 1 H), 2.66 (m, 2H), 2.37 (dd, J1=4.6, J2=16.7,1H), 2.15 (s, 3H), 2.06 (s, 3H), 1.20 (m, 6H). MS m/e(M-C₂H₄O₂+H)⁺=306.2.

2-(S)-(4-Acetoxymethyl-1H-indazol-5-ylmethyl)-succinic acid diethylester. Isoamyl nitrite (1.6 mL, 12 mmol) was added dropwise to a cooled(water ice bath) solution of2-(S)-(2-acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethylester in carbontetrachloride (80 mL) and acetic acid (4 mL). Mixture wasstirred at 0° C. for 2 hours. Mixture was warmed and stirred at ambienttemperature for 14 hours. Mixture was concentrated in vacuo. Residue wasdissolved in dichloromethane (75 mL) then washed successively withsaturated aqueous sodium bicarbonate (2×50 mL), and brine (30 mL).Organic was dried (magnesium sulfate), filtered and concentrated invacuo. Silica gel chromatography (ethyl acetate-hexanes) afforded theproduct in 55% yield as an amber oil. ¹H NMR (300 MHz, CDCl₃): δ=8.19(s, 1H), 7.44 (d, J=8.8, 1H), 7.24 (d, J=8.8, 1H), 5.49 (s, 2H), 4.06(m, 4H), 3.25 (m, 1H), 3.11 (m, 1H), 2.97 (m, 1H), 2.72 (dd, J1=8.8,J2=16.5, 1H) 2.43 (dd, J1=5.1, J2=16.5), 2.09 (s, 3H), 1.19 (m, 6H). MSm/e (M+H)⁺=377.1.

2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester. Potassium carbonate (1.6 g, 11.6 mmol) was added to a solution of2-(S)-(4-acetoxymethyl-1H-indazol-5-ylmethyl)-succinic acid diethylester (2.0 g, 5.5 mmol) in methanol (60 mL). Mixture was stirred at roomtemperature for 1.5 hours. Reaction was quenched with the addition of 1Nhydrochloric acid (30 mL). Methanol was removed from the mixture invacuo. Remaining aqueous was basified with sodium bicarbonate. Mixturewas extracted with ethyl acetate (2×40 mL). Combined organic layers werewashed successively with water (30 mL) and brine (30 mL). Organic wasdried (magnesium sulfate), filtered then concentrated in vacuo. Desiredproduct was obtained in 92% yield as an amber oil. ¹H NMR (300 MHz,CDCl₃): δ=8.21 ((s, 1 H), 7.34 (d, J=9.2, 1H), 7.17 (d, J=8.8, 1H), 5.02(dd, J1=12.4, J2=17.9, 1H) 3.63 (s, 6H), 3.23 (m, 1H), 2.98 (m, 1H),2.77 (dd, J1=7.7, J2=16.8, 1H), 2.53 (dd, J1=6.4, J2=16.7, 1H). MS m/e(M+H)⁺=307.0.

2-(S)-(4-Chloromethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester hydrochoride. Thionyl chloride (5.0 mL) was added to a solution of2-(S)-(4-hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester (1.53 g, 5.0 mmol) in dichloromethane (30 mL). Reaction mixturewas stirred at ambient temperature for 2 hours. Mixture was concentratedin vacuo. Residue was triturated in toluene (30 mL), then concentratedin vacuo. Residue was treated with dichloromethane (30 mL) thenconcentrated in vacuo. Desired product was obtained in 96% yield as anorange solid. ¹H NMR (300 MHz, CDCl₃): δ=8.22 (s, 1H), 7.49 (d, J=8.8,1H), 7.15 (d, J=8.8, 1H), 5.12 (s, 2H), 3.56 (s, 3H), 3.52 (s, 3H), 3.05(m, 3H), 2.69 (dd, J1=8.1, J2=16.5), 2.54 (m, 1H). MS m/e (M+H)⁺=325.2.

[9-(2,2-Dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Neopentylamine (2.0 mL, 17 mmol) was added to amixture of potassium carbonate (1.2 g, 8.7 mmol) and2-(S)-(4-chloromethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester hydrochloride (1.56 g, 4.3 mmol) in acetonitrile (30 mL). Reactionmixture was heated at reflux until starting material was deemed to beconsumed by HPLC. (1.5 hours). Mixture was cooled to room temperaturethen filtered. Filtrate was concentrated in vacuo. Residue was dissolvedin a mixture of toluene (40 mL) and acetic acid (2 mL). Reaction mixturewas heated at reflux until judged complete by HPLC. (44 hours). Mixturewas concentrated in vacuo. Residue was dissolved in ethyl acetate (50mL) and washed with saturated aqueous sodium bicarbonate (2×25 mL).Organic was dried (magnesium sulfate), filtered and concentrated invacuo. Silica gel chromatography (ethyl acetate-hexanes) yielded thedesired product in 90% yield as a yellow foam. ¹H NMR (300 MHz, CDCl₃):δ=8.01 (s, 1H), 7.35 (d, J=8.4, 1H), 7.13 (d, J=8.4, 1H), 5.41 (d,J=16.8, 1H), 4.50 (d, J=16.8, 1H), 3.90 (m, 1H), 3.70 (s, 3H), 3.62 (m,1H), 3.50 (d, J=13.9, 1H), 3.18 (d, J=13.5, 1H), 3.05 (m, 2H), 2.43 (dd,J1=16.7, J2=5.3, 1H), 0.83 (s, 9H). MS m/e (M−H)⁻=342.0.

[9-(2,2-Dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Lithium hydroxide monohydrate (335 mg, 8.0 mmol) was added to asolution of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (1.32 g, 3.8 mmol) in methanol (15 mL),tetrahydrofuran (15 mL) and water (15 mL). Reaction mixture was heatedat 50° C. for 1 hour. The organic solvents were removed from the mixturein vacuo. Remaining aqueous was diluted with water (25 mL). Mixture wasneutralized with 1 N hydrochloric acid (8.0 mL). Mixture was extractedwith ethyl acetate (2×30 mL). Combined organic layers were washed withbrine (20 mL) then dried (magnesium sulfate), filtered and concentratedin vacuo. Desired product was obtained in 88% yield as a light yellowsolid. ¹H NMR (300 MHz, CDCl₃): δ=7.98 (s, 1H), 7.36 (d, J=8.8, 1H),7.10 (d, J=8.8, 1H), 5.38 (d, J=16.8, 1H), 4.48 (d, J=16.8, 1H), 3.85(m, 1H), 3.49 (d, J=13.5, 1H), 3.18 (d, J=13.9, 1H), 3.08 (s, 2H), 2.92(dd, J1=8.2, J2=16.3, H), 2.55 (dd, J1=16.5, J2=4.8, 1H) 0.81 (s, 9H).MS m/e (M−H)⁻=328.0.

(9-Benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl)-aceticacid methyl ester. Benzylamine (250 μL, 2.3 mmol) and2-(S)-(4-Chloromethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester hydrochloride were converted following a procedure analogous tothe preparation of[9-(2,2-Dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Silica gel chromatography (ethyl acetate-hexanes)afforded the desired product in 62% yield as an amber oil. ¹H NMR (300MHz, CDCl₃): δ=7.77 (s, 1H), 7.28 (m, 6H), 7.09 (d, J=8.4, 1H), 5.18 (d,J=16.8, 1H), 4.99 (d, J=15.0, 1H), 4.43 (d, J=5.9, 1H), 4.39 (d, J=1.8,1H), 4.34 (d, J=4.0, 1H), 3.74 (s, 3H), 3.13 (m, 2H), 2.51 (dd, J1=5.5,J2=16.8, 1H). MS m/e (M+H)⁺=364.0.

(9-Benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl)-aceticacid. Lithium hydroxide (32 mg, 0.76 mmol) and(9-benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl)-aceticacid methyl ester were reacted in a manner analogous to the preparationof[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Desired product was obtained as a yellow oil in 99% yield. ¹H NMR(300 MHz, DMSO, D₆): δ=7.72 (s, 1H), 7.28 (m, 4H), 7.16 (m, 2H), 7.06(d, J=8.8, 1H), 5.15 (d, J=16.8, 1H), 4.95 (d, J=15.0, 1H), 4.37 (m,4H), 3.09 (m, 2H), 2.59 (dd, J1=5.1, J2=16.5, 1H). MS m/e (M+H)⁺=350.0.

[4-Chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Potassium carbonate (190 mg, 1.4 mmol) was added to asolution of2-(S)-(4-acetoxymethyl-7-chloro-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester (240 mg, 0.58 mmol) in methanol (10 mL) and ethanol (5mL). Mixture was stirred at room temperature for 1.5 hours. Reaction wasquenched with the addition of 1 N hydrochloric acid (10 mL). Organicsolvents were removed from the mixture in vacuo. Remaining aqueous wasbasified with sodium bicarbonate. Mixture was extracted 2× ethyl acetate(15 mL). Combined organic layers were dried (magnesium sulfate),filtered and concentrated. Residue was dissolved in dichloromethane (6mL). Thionyl chloride (2 mL) was added to the mixture. Reaction wasstirred at room temperature for 1.5 hours. Mixture was concentrated invacuo. Residue was treated with dichloromethane (25 mL) thenconcentrated in vacuo. Residue was suspended in acetonitrile (5 mL).Potassium carbonate (200 mg, 1.4 mmol) was added to the mixture followedby neopentylamine (150 μL, 1.3 mmol). Reaction mixture was heated atreflux for 1 hour. Mixture was cooled to room temperature then filteredthrough a 0.45 μm PTFE membrane. Filtrate was concentrated. Residue wasdissolved in a mixture of toluene (5 mL) and acetic acid (250 μL).Reaction mixture was heated at 100° C. for 15 hours then warmed toreflux for 7 hours. Mixture was cooled to room temperature then dilutedwith ethyl acetate (15 mL). Mixture was washed successively 2× saturatedaqueous sodium bicarbonate (20 mL), water (15 mL) and brine (10 mL).Organic was dried (magnesium sulfate), filtered and concentrated invacuo. Silica gel chromatography (ethyl acetate-hexanes) afforded thedesired product in 48% yield as a yellow oil. ¹H NMR (300 MHz, CDCl₃):δ=8.02 (s, 1H), 7.13 (s, 1H), 5.37 (m, 1H), 4.42 (d, J=17.2, 1H), 3.88(m, 1H), 3.70 (s, 3H), 3.53 (d, J=13.9, 1H), 3.12 (d, J=13.9, 1H), 3.03(m, 3H), 2.44 (dd, J1=5.9, J2=16.9, 1H), 0.81 (s, 9H). MS m/e(M+H)⁺=378.1.

[4-Chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Lithium hydroxide monohydrate (30 mg, 0.71 mmol) was added to asolution of[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (100 mg, 0.26 mmol) in methanol (2 mL),tetrahydrofuran (2 mL) and water (2 mL). Reaction mixture was stirred atambient temperature for two hours followed by heating at 50° C. for 40minutes. Organic solvents were removed from the mixture in vacuo.Remaining aqueous was neutralized with 1N hydrochloric acid (750 μL).Mixture was extracted 2× ethyl acetate (10 mL). Combined organic layerswere washed with brine (10 mL) then dried (magnesium sulfate), filteredand concentrated in vacuo. Desired product was obtained in 93% yield asan orange solid. ¹H NMR (300 MHz, CDCl₃): δ=7.98 (s, 1H), 7.09 (s, 1H),5.35 (d, J=17.2, 1H), 4.41 (d, J=17.2, 1H), 3.82 (m, 1H), 3.48 (d,J=13.9, 1H), 3.12 (d, J=13.9, 1H), 3.02 (m, 2H), 2.92 (dd, J1=8.4,J2=16.8, 1H), 2.45 (dd, J1=5.1, J2=16.8, 1H), 0.78 (s, 9H). MS m/e(M−H)⁻=362.0.

3-(2-Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester. Palladium (II) acetate (105 mg, 0.43 mmol) was addedto a mixture of acetic acid3-tert-butoxycarbonylamino-6-iodo-2-methyl-benzyl ester (2.89 g, 7.1mmol), Z-dehydroalanine methyl ester (2.20 g, 9.4 mmol),tetrabutylammonium chloride hydrate (2.70 g, 9.7 mmol), and sodiumbicarbonate (1.80 g, 21.4 mmol) in THF (100 mL). Reaction was heated atreflux for 3.75 hours. Mixture was cooled to room temperature thenfiltered through a plug of silica gel eluting 70% ethyl acetate-hexanes(500 mL). Filtrate was concentrated in vacuo. Silica gel chromatographyafforded the title compound as a yellow solid in 69% yield. ¹H NMR (300MHz, CDCl₃): δ=7.79 (d, J=8.4, 1H), 7.42 (s, 1H), 7.27 (m, 6H), 6.30 (s,1H), 5.11 (s, 2H), 5.02 (s, 2H), 3.81 (s, 3H), 2.21 (s, 3H), 2.02 (s,3H), 1.51 (s, 9H). MS m/e (M−H)⁻=511.0.

3-(2-Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester. A solution of3-(2-acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-benzloxycarbonylamino-acrylicacid methyl ester (2.51 g, 4.9 mmol) in methanol (50 mL) and ethylacetate (15 mL) was reacted in a manner similar to the preparation of2-(S)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester. Title compound was obtained as an off-white solid in97% yield. ¹H NMR (300 MHz, CDCl₃): δ=7.66 (d, J=7.9, 1H), 7.31 (m, 5H),6.99 (d, J=8.5, 1H), 6.21 (s, 1H), 5.31 (d, J=7.6, 1H), 5.17 (d, J=3.7,2H), 5.04 (d, J=5.80, 2H), 4.56 (m, 1H), 3.71 (s, 3H), 3.23 (dd,J1=5.80, J2=14.7, 1H), 3.07 (dd, J1=7.8, J2=14.2, 1H), 2.21 (s, 3H),2.00 (s, 3H), 1.50 (s, 9H). MS m/e (M−H)⁻=513.0.

3-(4-Acetoxymethyl-1H-indazol-5-yl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester. Trifluoroacetic acid (2.5 mL) was added to a solutionof3-(2-acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester (770 mg, 1.5 mmol) in dichloromethane (10 mL).Reaction mixture was stirred at room temperature for 1.5 hours. Mixturewas concentrated in vacuo. Residue was treated with chloroform (40 mL)then concentrated in vacuo. Residue was dissolved in 5% acetic acid inchloroform (10 mL). Isoamyl nitrite (240 μL, 1.8 mmol) was added to themixture. Reaction mixture was stirred at ambient temperature for 20minutes. Potassium acetate (690 mg, 7.0 mmol) was added to the mixture.Reaction mixture was stirred at ambient temperature for 45 minutes.Mixture was washed successively with water (10 mL), and 2× saturatedaqueous sodium bicarbonate (15 mL). Organic was dried (magnesiumsulfate), filtered and concentrated. Crude product was obtained in 81%yield as an amber oil and was used without further purification. ¹H NMR(300 MHz, CDCl₃): δ=8.17 (s, 1H), 7.41 (d, J=8.4, 1H), 7.25 (m, 6H),5.54 (d, J=8.1, 1H), 5.44 (s, 2H), 5.03 (s, 2H), 4.67 (m, 1 H), 3.78 (s,3H), 3.37 (dd, J1=5.9, J2=14.3, 1H), 3.22 (dd, J1=8.1, J2=14.3, 1H),1.98 (s, 3H). MS m/e (M+H)⁺=426.0.

2-(R)-Benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionicacid methyl ester hydrochloride. Potassium carbonate (1.65 g, 12 mmol)was added to a solution of3-(4-acetoxymethyl-1H-indazol-5-yl)-2-benzyloxycarbonylamino-propionicacid methyl ester (2.30 g, 5.4 mmol) in methanol (70 mL). Reactionmixture was stirred at room temperature for 2 hours. Reaction wasquenched with 1N hydrochloric acid (50 mL). Methanol was removed fromthe mixture in vacuo. Remaining aqueous was basified with sodiumbicarbonate. Aqueous was extracted with ethyl acetate (2×50 mL).Combined extracts were washed with water (30 mL) and brine (20 mL).Organic was dried (magnesium sulfate), filtered and concentrated.Residue was dissolved in 1:1 ethyl acetate:hexanes (50 mL). 1Nhydrochloric acid in 1,4 dioxane (1.4 mL), was added to the mixturedropwise causing a precipitate to form. Mixture was stirred at roomtemperature for 1 hour. Solids were filtered, washed with 1:1 ethylacetate:hexanes, then dried in vacuo. Product was obtained in 61% yieldas a tan solid. ¹H NMR (300 MHz, DMSO-D₆): δ=8.67 (s, 1H), 7.49 (s, 2H),7.22 (m, 5H), 4.99 (m, 4H), 4.50 (m, 1H), 3.73 (s, 3H), 3.41 (m, 1H),3.13 (dd, J1=9.9, J2=13.9, 1H). MS m/e (M+H)⁺=384.0.

2-(R)-Benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester hydrochloride.2-(R)-Benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionicacid methyl ester hydrochloride was reacted in a manner analogous to thepreparation of 2-(S)-(4-chloromethyl-1H-indazol-5-ylmethyl)-succinicacid dimethyl ester hydrochloride. Title compound was obtained as anorange solid in 99% yield. ¹H NMR (300 MHz, CD₃OD): δ=8.43 (s, 1H), 7.50(d, J=8.8, 1H), 7.38 (d, J=8.4, 1H), 7.24 (m, 5H), 5.06 (d, J=11.0, 1H),4.98 (d, J=4.8, 2H), 4.56 (dd, J1=5.7, J2=9.3, 1H), 3.71 (s, 3H), 3.42(dd, J1=5.5, J2=14.3, 1H), 3.17 (dd, J1=9.3, J2=14.1, 1H). MS m/e(M+H)⁺=402.0.

[9-(2,2-Dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. Neopentylamine (600 μL, 4.5 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester hydrochloride were reacted in a manner analogous tothe preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Silica gel chromatography afforded the title compoundas a lightly colored oil in 88% yield. ¹H NMR (300 MHz, CDCl₃): δ=7.97(d, J=2.9, 1H), 7.38 (d, J=4.0, 3H), 7.31 (m, 3H), 7.06 (dd, J1=3.7,J2=8.8, 6.32 (d, J=6.3, 1H), 5.24 (m, 2H), 5.15 (s, 2H), 4.42 (dd,J1=5.5, J2=17.2, 1H), 3.56 (d, J=13.9, 1H), 3.45 (d, J=16.5, 1H), 3.07(m, 2H), 0.82 (s, 9H). (M+H)⁺=421.0.

7-(R)-Amino-9-(2,2-dimethyl-propyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethanesulfonate. Methanesulfonic acid (1 mL) was added to a solutionof[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (145 mg, 0.34 mmol) and anisole (100 μL, 0.92 mmol) indichloromethane (4 mL). Reaction mixture was stirred at room temperaturefor 2.5 hours. Mixture was diluted with diethyl ether (25 mL). Mixturewas allowed to stand at room temperature for 30 minutes. Solvents weredecanted off. Remaining residue was washed with diethyl ether (25 mL)then dried in vacuo. Crude product was obtained as an orange oil inquantitative yield, and was used without further purification. ¹H NMR(300 MHz, CD₃OD): δ=8.50 (s, 1H), 7.56 (d, J=8.8, 1H), 7.39 (s, J=8.8,1H), 5.42 (d, J=17.9, 1H), 5.10 (dd, J=4.4, J2=12.4, 1H), 4.75 (d,J=17.6, 1H), 3.84 (d, J=13.5, 1H), 3.42 (m, 3H), 3.10 (d, J=13.9, 1H),2.71 (s, 6H), 0.82 (s, 9H). (M+H)⁺=287.1.

(3-Acetyl-9-benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester. Benzylamine (53 μL, 0.49 mmol) was added to a mixtureof2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (125 mg, 0.31 mmol) and potassium carbonate (50 mg,0.36 mmol) in acetonitrile (5 mL). Reaction was heated at reflux for 1hour. Mixture was cooled to room temperature then filtered. Filtrate wasconcentrated. Residue was dissolved in a mixture of toluene (5 mL) andacetic acid (50 μL). Mixture was heated at reflux for 2 hours. Mixturewas cooled to room temperature. Acetic anhydride (500 μL) was added tothe mixture. Reaction was stirred at room temperature for 2 hours.Mixture was diluted with ethyl acetate (20 mL). Mixture was washedsuccessively with water (15 mL), 1N hydrochloric acid (2×10 mL), andbrine (10 mL). Organic was dried (magnesium sulfate), filtered andconcentrated. Silica gel chromatography (ethyl acetate-hexanes) yieldedthe title compound in 43% yield as an amber oil. ¹H NMR (300 MHz,CDCl₃): δ=8.33 (s, 1H), 7.47 (d, J=8.8, 1H), 7.33 (m, 5H), 7.17 (m, 5H),7.02 (d, J=9.2, 1H), 6.28 (d, J=6.6, 1H), 5.34 (m, 1H), 5.16 (s, 2H),5.00 (m, 1H), 4.84 (m, 1H), 5.43 (t, J=14.5, 1H), 4.43 (d, J=5.9, 1H),4.32 (d, J=16.8, 1h), 4.11 (m, 1H), 2.02 (s, 3H). MS m/e (M+H)⁺=483.2.

(3-Acetyl-9-methyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester. Methylamine solution in methanol (2M, 2 mL, 4 mmol)was added to a mixture of potassium carbonate (130 mg, 0.94 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (165 mg, 0.41 mmol) in acetonitrile (5 mL). Mixturewas heated at 40° C. for 1 hour. Mixture was cooled to room temperature.Mixture was filtered. Filtrate was concentrated. Residue was treatedwith a mixture of toluene (5 mL) and acetic acid (200 μL). Mixture washeated at reflux for 45 minutes. Mixture was cooled to room temperaturethen acetic anhydride was added (2 mL). Reaction was stirred at roomtemperature for 16 hours. Mixture was diluted with ethyl acetate (10 mL)then washed successively with water (10 mL), saturated aqueous sodiumbicarbonate (2×15 mL) and brine (10 mL). Organic was dried (magnesiumsulfate), filtered and concentrated. Silica gel chromatography (ethylacetate-hexanes) yielded the desired product as a yellow solid in 18%yield. ¹H NMR (300 MHz, CDCl₃): δ=8.70 (s, 1H), 7.51 (d, J=9.2, 1H),7.34 (m, 5H), 7.05 (d, J=9.2, 1 H), 6.19 (m, 1H), 5.23 (s, 2H), 5.13 (s,2H), 4.18 (d, J=17.2, 1H), 3.46 (d, J=17.2, 1H), 3.11 (s, 3H), 2.95 (m,1H), 2.89 (s, 3H). MS m/e (M+H)⁺=407.2.

[8-Oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. 1-(2-Aminoethyl)piperidine (150 μL, 1.1 mmol) wasadded to a mixture of potassium carbonate (150 mg, 1.1 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester hydrochloride (220 mg, 0.50 mmol) in acetonitrile (5mL). Reaction was heated at reflux for 1 hour. Mixture was cooled toroom temperature then concentrated. Residue was dissolved in a mixtureof dichloromethane (10 mL) and acetic acid (200 μL). Mixture was heatedat 40° C. for 32 hours and heated at reflux for 8 hours. Mixture wascooled to room temperature then washed successively with saturatedaqueous sodium bicarbonate (2×10 mL), water (10 mL) and brine (10 mL).Organic was dried (magnesium sulfate), filtered and concentrated. Crudeproduct was obtained as a maroon solid in 86% yield. Material wascarried forward without further purification. MS m/e (M+H)⁺=462.4. HPLC.rf=1.19 min.

7-(R)-Amino-9-(2-piperidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Methanesulfonic acid (1 mL) was added to a mixture of anisole (100 μL,0.92 mmol) and[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (200 mg, 0.43 mmol) in dichloromethane (4 mL).Reaction was stirred at ambient temperature for 1 hour. Mixture wasdiluted with diethyl ether (30 mL). Mixture was allowed to stand at roomtemperature for 15 minutes. Solvents were decanted off. Remainingresidue was dissolved in water (5 mL). Mixture was washed with diethylether (2×10 mL). Aqueous was basified with 1N sodium hydroxide (2 mL).Mixture was extracted with ethyl acetate (2×15 mL). Combined extractswere washed with brine (5 mL). Organic was dried (magnesium sulfate),filtered and concentrated. Title compound was obtained as an amber oilin 42% yield. Material was carried forward without further purification.¹H NMR (300 MHz, CDCl₃): δ=8.06 (S, 1H), 7.35 (d, J=8.4, 1H), 7.11 (d,J=8.4, 1H), 5.16 (d, J=16.8, 1H), 4.57 (d, J=16.8, 1H), 4.40 (dd,J1=12.8, J2=4.4, 1H), 3.77 (m, 1H), 3.54 (m, 1H), 3.29 (m, 1H), 3.03 (m,1H), 2.36 (m, 6H), 2.14 (m, 2H), 1.38 (m, 4H). MS m/e (M+H)⁺=328.3.

[8-Oxo-9-(2-pyrrolidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. 1-(2-Aminoethyl)pyrrolidine (90 μL, 0.71 mmol) wasadded to a mixture of2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (100 mg, 0.23 mmol) and potassium carbonate (120 mg,0.87 mmol) in acetonitrile (5 mL). Reaction was heated at reflux untilHPLC suggested the starting material had been consumed (2 hours).Mixture was cooled to room temperature then filtered. Acetic acid (200μL) was added to the filtrate. Reaction was heated at reflux untiljudged complete by HPLC. (1 hour). Mixture was diluted with ethylacetate (20 mL) then washed successively with saturated aqueous sodiumbicarbonate (15 mL), water (10 mL) and brine (10 mL). Organic was dried(magnesium sulfate), filtered and concentrated. Crude product wasobtained in 69% yield as a yellow oil. Material was carried forwardwithout further purification. 1H NMR (300 MHz, CDCl₃): δ=8.04 (s, 1),7.38 (m, 5H), 7.28 (d, J=8.4, 1H), 7.02 (d, J=8.8, 1H), 6.25 (d, J=6.2,1H), 5.25 (m, 1H), 5.15 (s, 2H), 4.56 (d, J=16.8, 1H), 3.70 (m, 2H),3.47 (dd, J1=3.5, J2=16.7, 1H), 3.01 (m, 1H), 2.62 (m, 2H), 2.48 (m,3H), 1.74 (m, 4H). MS m/e (M+H)⁺=448.4.

7-(R)-Amino-9-(2-pyrrolidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained from[8-oxo-9-(2-pyrrolidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester following a procedure analogous to the preparation of7-(R)-amino-9-(2-piperidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as an amber oil in 52% yield and used withoutfurther purification. ¹H NMR (300 MHz, DMSO-D₆): δ=8.06 (s, 1H), 7.33(d, J=8.8, 1H), 7.10 (d, J=8.8, 1H), 5.16 (d, J=16.8, 1H), 5.48 (d,J=16.8, 1H), 4.40 (dd, J1=13.0, J2=4.2, 1H), 3.67 (m, 2H), 3.29 (dd,J1=3.11, J2=17.0, 1H), 3.01 (dd, J1=16.8, J2=12.8, 1H), 2.58 (m, 2H)m1.87 (m, 4H), 1.67 (m, 4H). MS m/e (M+H)⁺=422.4.

[9-(2-Dimethylamino-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. N,N-Ethylenediamine (70 μL, 0.66 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (100 mg, 0.23 mmol) were converted to the titlecompound following a procedure analogous to the preparation of[8-oxo-9-(2-pyrrolidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. Crude product was obtained as an amber oil in 52%yield. Material was carried forward without further purification. ¹H NMR(300 MHz, CDCl₃): δ=7.99 (s, 1H), 7.36 (m, 6H), 6.27 (d, J=6.2, 1H),5.25 (m, 1H), 5.16 (s, 2H), 5.13 (m, 1H), 5.06 (d, J=18.7, 1H), 4.52 (d,J=17.2, 1H), 3.61 (t, J=6.8, 2H), 3.45 (dd, J1=2.4, J2=16.7, 1H), 3.01(m, 1H), 2.38 (m, 2H), 2.11 (s, 6H). MS m/e (M+H)⁺=422.4.

7-(R)-Amino-9-(2-dimethylamino-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.[9-(2-Dimethylamino-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (65 mg, 0.15 mmol) was converted to the desiredproduct in a manner analogous to the preparation of7-(R)-amino-9-(2-pyrrolidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Crude material was obtained as a yellow oil in 25% yield. Material wascarried forward without further purification. ¹H NMR (300 MHz, CDCl₃):δ=8.07 (s, 1H), 7.35 (d, J=8.4, 1H), 7.12 (d, J=8.4, 1H), 5.15 (d,J=16.8, 1H), 4.58 (d, J=16.8, 1H), 4.42 (dd, J1=4.8, J2=12.8, 1H), 3.62(m, 2H), 3.30 (m, 1H), 3.01 (dd, J1=13.0, J2=16.7, 1H), 2.37 (m, 2H),2.15 (s, 6H). MS m/e (M+H)⁺=288.3.

[9-(2-Morpholin-4-yl-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. 4-(2-Aminoethyl)morpholine (90 μL, 0.69 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (100 mg, 0.23 mmol) were converted into the titlecompound following a procedure analogous to the preparation of[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. Crude material was obtained as an amber oil in 92%yield. Product was carried forward without further purification. MS m/e(M+H)⁺=464.4. HPLC. rf=1.15 min.

7-(R)-Amino-9-(2-morpholin-4-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.[9-(2-Morpholin-4-yl-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (95 mg, 0.20 mmol) was converted into the titlecompound following a procedure analogous to the preparation of7-(R)-amino-9-(2-piperidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Crude product was obtained as an amber oil in 62% yield. Material wascarried forward without further purification. ¹H NMR (300 MHz, CDCl₃):δ=8.06 (s, 1H), 7.34 (d, J=8.4, 1H), 7.15 (d, J=8.8, 1H), 5.22 (d,J=16.8, 1H), 4.51 (d, J=17.2, 2H), 4.44 (m, 1H), 4.02 (m, 1H), 3.40 (t,J=4.8, 4H), 3.31 (m, 3H), 3.07 (m, 1H), 2.32 (m, 4H), 1.95 (m, 2H). MSm/e (M+H)⁺=330.3.

[8-Oxo-9-(1-(S)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. (S)-(−)-α-Methylbenzylamine (85 μL, 0.67 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (100 mg, 0.23 mmol) were converted into the desiredproduct following a procedure analogous to the preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Crude product was obtained as a dark oil inquantitative yield. Material was carried forward without furtherpurification. MS m/e (M+H)⁺=455.3. HPLC. rf=1.68 min.

7-Amino-9-(1-(S)-phenyl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-8-one.[8-Oxo-9-(1-(S)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (105 mg, 0.23 mmol) was reacted in a manner analogousto the preparation of7-(R)-amino-9-(2-piperidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Crude product was obtained as a dark oil in 82% yield. Material wascarried forward without further purification. MS m/e (M−H)⁻=319.3. HPLC.rf=1.49 min.

[8-Oxo-9-(1-(R)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. (R)-(+)-α-Methylbenzylamine (85 μL, 0.67 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (100 mg, 0.23 mmol) were converted into the titlecompound in a manner similar to the preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Crude material was obtained as a dark foam inquantitative yield. Material was carried forward without furtherpurification. MS m/e (M−H)⁻=453.4. HPLC. rf=1.98 min.

7-Amino-9-(1-(R)-phenyl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-8-one.[8-Oxo-9-(1-(R)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (105 mg, 0.23 mmol) was reacted in a manner analogousto the preparation of7-(R)-amino-9-(2-piperidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Crude product was obtained as a maroon solid in 78% yield. Material wascarried forward without further purification. ¹H NMR (300 MHz, CDCl₃):δ=7.88 (s, 1H), 7.40 (m, 6H), 7.14 (d, J=8.8, 1H), 6.85 (m, 1H), 6.09(m, 1H), 4.67 (d, J=16.8, 1H), 4.47 (dd, J1=4.6, J2=12.6, 1H), 4.25 (d,J=17.2, 1H), 1.48 (d, J=7.0, 3H). MS m/e (M−H)⁻=319.3.

[8-Oxo-9-(4-trifluoromethyl-benzyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. 4-Trifluoromethylbenzylamine (72 μL, 0.51 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (100 mg, 0.23 mmol) were converted into the titlecompound in a manner similar to the preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Crude material was obtained as a dark brown solid inquantitative yield. Material was carried forward without furtherpurification. MS m/e (M+H)⁺=509.4. HPLC. rf=1.67 min.

7-Amino-9-(4-trifluoromethyl-benzyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-8-onebis-methanesulfonate.[8-Oxo-9-(4-trifluoromethyl-benzyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester was converted into the title compound in a manneranalogous to the preparation of7-(R)-amino-9-(2,2-dimethyl-propyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethaneslufonate. Crude material was obtained as a dark foam inquantitative yield. Material was carried forward without furtherpurification. MS m/e (M+H)⁺=375.2. HPLC. rf=1.00 min.

(9-Isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester. Isopropylamine (300 μL, 3.5 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester were converted into the title compound following aprocedure analogous to the preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Crude product was obtained as a dark oil inquantitative yield. Material was carried forward without furtherpurification. ¹H NMR (500 MHz, CDCl₃): δ=8.09 (s, 1H), 7.39 (m, 3H),7.23 (m, 2H), 7.17 (m, 1H), 6.32 (d, J=5.8, 1H), 5.25 (m, 1H), 5.15 (m,2H), 4.90 (m, 1H), 4.82 (d, J=17.4, 1H), 4.51 (m, 1H), 3.51 (m, 1H),3.05 (t, J=13.6, 1H), 1.56 (s, 6H). MS m/e (M+H)⁺=393.4.

7-(R)-Amino-9-isopropyl-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethanesulfonate.(9-Isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester (90 mg, 0.23 mmol) was converted into the titlecompound following a procedure analogous to the synthesis of7-(R)-amino-9-(2,2-dimethyl-propyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethaneslufonate. Crude product was obtained as a dark oil inquantitative yield. Crude material was carried forward without furtherpurification. MS m/e (M+H)⁺=259.2. HPLC. rf=0.60 min.

[9-(3,3-Dimethyl-butyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. 3,3-Dimethylbutylamine (100 μL, 0.74 mmol) and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester were converted into the title compound following aprocedure analogous to the preparation of[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. Crude material was obtained as a dark oil inquantitative yield. Material was carried forward without furtherpurification. ¹H NMR (300 MHz, CDCl₃): δ=8.03 (m, 1H), 4.38 (m, 4H),7.31 (m, 2H), 7.06 (d, J=8.4, 1H), 6.26 (d, J=6.2, 1H), 5.23 (m, 1H),5.14 (s, 2H), 5.08 (m, 1H), 4.35 (dd, J1=8.8, J2=17.2, 1H), 3.50 (m,2H), 1.33 (dd, J1=6.2, J2=11.0, 2H), 0.91 (m, 2H), 0.85 (s, 9H). MS m/e(M+H)⁺=435.1.

7-(R)-Amino-9-(3,3-dimethyl-butyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethanesulfonate.[9-(3,3-Dimethyl-butyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (100 mg, 0.23 mmol) was converted into the titlecompound following a procedure analogous to the preparation of7-(R)-amino-9-(2,2-dimethyl-propyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethaneslufonate. Crude material was obtained as a dark oil inquantitative yield. Material was carried forward without furtherpurification. MS m/e (M+H)⁺=301.2. HPLC. rf=1.11 min.

4-(7-(R)-Benzyloxycarbonylamino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylicacid tert-butyl ester. 4-Amino-1-N-Boc-piperidine (110 mg, 0.55 mmol)and2-(R)-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (150 mg, 0.34 mmol) was converted into the titlecompound in a manner analogous to the preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Crude product was obtained as a dark foam inquantitative yield. Material was carried forward without furtherpurification. ¹H NMR (300 MHz, CDCl₃): δ=8.05 (m, 1H), 7.35 (m, 6H),7.15 (m, 1H), 6.27 (m, 1H), 5.28 (m, 1H), 5.15 (s, 2H), 4.87 (d, J=16.5,1H), 4.63 (m, 1H), 4.47 (m, 1H), 4.24 (m, 1H), 3.99 (m, 1H), 3.49 (m,1H), 3.04 (m, 1H), 2.83 (m, 2H), 2.63 (m, 1H), 1.90 (m, 1H), 1.74 (m,2H), 1.58 (s, 9H). MS m/e (M−H)⁻=532.1.

4-(7-(R)-Amino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylicacid tert-butyl ester acetate. A catalytic amount of 10% palladium oncarbon was added to a solution of4-(7-(R)-Benzyloxycarbonylamino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylicacid tert-butyl ester (200 mg, 0.37 mmol) and acetic acid (100 μL, 1.7mmol) in methanol (10 mL). Reaction vessel was placed on a Parrapparatus and charged with 30 psi of hydrogen gas. Mixture was allowedto shake at room temperature for 3 hours. Mixture was filtered. Filtratewas concentrated in vacuo. Crude compound was obtained as a dark oil inquantitative yield. Material was carried forward without furtherpurification. ¹H NMR (300 MHz, CDCl₃): δ=8.06 (s, 1H), 7.36 (d, J=8.8,1H), 7.12 (d, J=8.8, 1H), 4.92 (d, J=17.6, 1 H), 4.67 (m, 1H), 4.49 (d,J=17.2, 1H), 4.26 (m, 1H), 3.98 (m, 2H), 3.05 (m, 1H), 2.83 (m, 2H),2.64 (m, 1H), 1.89 (m, 1H), 1.73 (m, 1H), 1.45 (d, J=2.9, 9H), 1.25 (m,2H). MS m/e (M−C₄H₈+H)⁺=344.2.

3-(2-Acetoxymethyl-4-amino-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester.3-(2-Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester was converted into3-(2-Acetoxymethyl-4-amino-3-methyl-phenyl)-2-benzyloxycarbonylamino-(R)-propionicacid methyl ester following an analogous procedure to the synthesis of2-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-(S)-succinic acid diethylester. Desired product was obtained as an yellow oil in 95% yield. ¹HNMR (300 MHz, CDCl₃): δ=7.31 (m, 5H); 6.81 (d, J=8.1, 1 H); 6.65 (d,J=8.4, 1H); 5.35 (d, J=8.1, 1H); 5.15 (s, 2H); 5.04 (s, 2H); 4.53 (m,1H); 3.71 (s, 3H); 3.16 (m, 1H); 3.01 (m, 1H); 2.12 (s, 3H); 1.99 (s,3H). MS m/e (M+H)⁺=415.2

3-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester. Desired product was obtained from3-(2-Acetoxymethyl-4-amino-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester in a manner analogous to the preparation of2-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-(S)-succinic aciddiethyl ester. Silica gel chromatography (ethyl acetate-hexanes)afforded the product as an yellow oil in 40% yield. ¹H NMR (300 MHz,CDCl₃): δ=7.31 (m, 5H); 6.96 (s, 1H); 5.36 (d, J=8.4, 1H); 5.12 (s, 2H);5.05 (s, 2H), 4.53 (m, 1H); 3.72 (s, 3H); 3.15 (m, 1H), 2.99 (m, 1H);2.15 (s, 3H); 1.99 (s, 3H). MS m/e (M−C₂H₄O₂+H)⁺=398.3.

3-(4-Acetoxymethyl-7-chloro-1H-indazol-5-yl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester. Trifluoroacetic acid (70 μL, 0.91 mmol) was added toa solution of3-(2-acetoxymethyl-4-amino-5-chloro-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester (345 mg, 0.77 mmol) in 5% acetic acid in chloroform(5.2 mL). Isoamyl nitrite (120 μL, 0.89 mmol) was added to the mixturedrop-wise. Reaction mixture was stirred at room temperature for 40minutes. Potassium acetate (300 mg, 3.1 mmol) was added to the mixture.Reaction mixture was stirred at room temperature for 45 minutes. Mixturewas diluted with dichloromethane (10 mL) then washed successively withwater (2×10 mL), and saturated aqueous sodium bicarbonate (2×10 mL).Organic was dried (magnesium sulfate), filtered and concentrated invacuo. Crude product was obtained as an orange solid in 83% yield.Material was carried forward without further purification. ¹H NMR (300MHz, CDCl₃): δ=8.20 (s, 1H); 7.29 (m, 5H); 7.21 (s, 1H); 5.53 (d, J=7.7,1H); 5.40 (s, 2H); 5.04 (s, 2H); 4.67 (m, 1H); 3.74 (s, 3H); 3.34 (m,1H); 3.21 (m, 1H); 2.02 (s, 3H). MS m/e (M+H)⁺=460.1.

2-(R)-Benzyloxycarbonylamino-3-(7-chloro-4-hydroxymethyl-1H-indazol-5-yl)-propionicacid methyl ester.3-(4-Acetoxymethyl-7-chloro-1H-indazol-5-yl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester (290 mg, 0.63 mmol) was converted into the desiredproduct in a manner analogous to the preparation of2-(R)-benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionicacid methyl ester. Crude product was obtained as an orange solid in 95%yield. Material was carried forward without further purification.

¹H NMR (300 MHz, CDCl₃): δ=8.15 (s, 1H); 7.27 (m, 5H); 7.14 (s, 1H);6.10 (m, 1H); 5.01 (d, J=4.8, 2H); 4.95 (s, 2H); 4.75 (m, 1H); 3.79 (s,3H); 3.34 (m, 1H); 3.09 (m, 1H). MS m/e (M+H)⁺=418.0.

2-(R)-Benzyloxycarbonylamino-3-(7-chloro-4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester. Thionyl chloride (2 mL) was added to a solution of2-(R)-benzyloxycarbonylamino-3-(7-chloro-4-hydroxymethyl-1H-indazol-5-yl)-propionicacid methyl ester (245 mg, 0.59 mmol) in dichloromethane (3 mL). Mixturewas stirred at room temperature for 1.5 hours. Mixture was concentrated.Residue was dissolved in dichloromethane (15 mL) then washed withsaturated aqueous sodium bicarbonate (2×10 mL). Organic was dried(magnesium sulfate), filtered and concentrated. Title compound wasobtained as an orange solid in 86% yield. Material was carried forwardwithout further purification. ¹H NMR (300 MHz, CDCl₃): δ=8.19 (s, 1H),7.32 (m, 5H), 7.16 (s, 1H), 5.49 (d, J=7.3, 2H), 5.07 (d, J=4.4, 2H),4.85 (s, 2H), 4.68 (d, J=7.0, 1H), 3.72 (s, 3H), 3.27 (m, 2H). MS m/e(M+H)⁺=436.1.

[4-Chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. Neopentylamine (200 μL, 1.7 mmol) was added to amixture of2-(R)-benzyloxycarbonylamino-3-(7-chloro-4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (180 mg, 0.41 mmol) and potassium carbonate (160 mg,1.2 mmol) in acetonitrile (5 mL). Reaction was heated at reflux for 1hour. Mixture was cooled to room temperature then filtered through a0.45 μm PTFE syringeless filter system. Filtrate was concentrated.Residue was dissolved in a mixture of toluene (5 mL) and acetic acid(200 μL). Mixture was heated at 110° C. overnight. Mixture was dilutedwith ethyl acetate (15 mL) then washed successively with water (15 mL),saturated aqueous sodium bicarbonate (2×15 mL) and brine (10 mL).Organic was dried (magnesium sulfate), filtered and concentrated. Silicagel chromatography afforded the title compound in 52% yield as a yellowsolid. ¹H NMR (300 MHz, CDCl₃): δ=7.89 (d, J=10.6, 1H), 7.38 (m, 5H),6.96 (d, J=10.3, 1H), 6.35 (d, J=5.9, 1H), 5.25 (m, 1H), 5.19 m, 2H),4.28 (m, 1H), 3.66 (m, 1H), 3.40 (m, 1H), 2.96 (dd, J1=13.9, J2=5.5,2H), 0.7 (d, J=2.6, 9H). MS m/e (M+H)⁺−455.2.

(9-Benzyl-4-chloro-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester. Title compound was obtained from benzylamine (100 μL,0.92 mmol) and2-(R)-Benzyloxycarbonylamino-3-(7-chloro-4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester (210 mg, 0.48 mmol) following a procedure analogous tothe preparation of[4-Chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester. Silica gel chromatography (ethyl acetate-hexanes)afforded the desired product as a yellow solid in 52% yield. ¹H NMR (300MHz, CDCl₃): δ=7.64 (s, 1H), 7.38 (m, 5H), 7.19 (m, 3H), 7.12 (m, 2H),7.00 (s, 1H), 6.36 (d, J=6.2 1H), 5.28 (m, 1H), 5.21 (s, 2H), 5.19 (m,1H), 4.88 (m, 1H), 4.75 (d, J=16.8, 1H), 4.34 (d, J=14.6, 1H), 3.49 (m,1H), 3.03 (m, 1H). MS m/e (M+H)⁺=475.0.

Acetic acid 3-acetylamino-6-iodo-2,4-dimethyl-benzyl ester. To a wellstirred solution of (3-amino-2,4-dimethyl-phenyl)-methanol (1.5 g) inmethanol (70 mL) and solid sodium hydrogen carbonate (4.0 eq) was addeda 1.0 M solution of iodine monochloride dropwise over a period of 5 minat 0° C. The cooling bath was removed after the addition of iodinemonochloride. The reaction mixture was brought to room temperature andstirring continued for another 1 h. The reaction mixture wasconcentrated to remove most of methanol, diluted with dichloromethane(50 mL) and washed with 10% solution of sodium thiosulfate and dried(Na2SO4). The desired compound was purified by trituration withdichloromethane and hexane to give in 1.9 g of iodide. The iodide wasthen treated with dichloromethane (100 mL) followed by acetic anhydride(4 eq) and catalytic amount of dimethylaminopyridine and stirred for aperiod of 12 h at room temperature. The reaction mixture was then washedwith aqueous sodium hydrogen carbonate, 1.0 M hydrochloric acid anddried (Na2SO4). The desired compound was triturated with dichloromethaneand hexane to give acetic acid 3-acetylamino-6-iodo-2,4-dimethyl-benzylester in 95% yield. ¹H NMR (300 MHz, CDCl₃): in δ 7.68 (s, 1 H), 6.68(s, 1 H), 2.28 (s, 3 H), 2.25 (s, 3 H), 2.18 (s, 3 H), 2.07(s, 3 H); MS(ESI) 384 (M+Na); R_(f)=1.12.

Acetic acid 5-benzyloxy-2-iodo-benzyl ester. To a well stirred solutionof 3-benzyloxybenzyl alcohol (5.5 g, 25.7 mmol) in methanol (100 mL) andsodium hydrogencarbonate (8.4 g, 100 mmol) was added a 1.0 M solution ofiodine monochloride in dichloromethane (30 mL) at 0° C. The reactionmixture was brought to room temperature and stirring continued foradditional 1 h. The reaction mixture was concentrated and then dilutedwith dichloromethane (150 mL), washed with 10% aqueous sodiumthiosulfate and dried (Na₂SO₄). The desired compound was purified byflash chromatography (silica) using 20% ethyl acetate in hexane to give5-benzyloxy-2-iodobenzyl alcohol (6.2 g, 71% yield). The alcohol (4.2 g,12.4 mmol) was dissolved in dichloromethane (100 mL) added aceticanhydride (2.52 g, 24.7 mmol) and catalytic amount of4-dimethylaminopyridine. The reaction mixture was then stirred for 12 h,washed with aqueous sodium hydrogencarbonate and then dried (Na₂SO₄) togive acetic acid 5-benzyloxy-2-iodo-benzyl ester in quantitative yield.MS (ESI) 405 (M+Na) ; R_(f)=2.27.

3-(2-Acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-acrylicacid methyl ester. In a manner similar to2-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzylidene)-succinicacid diethyl ester,3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-acrylicacid methyl ester was prepared by reacting acetic acid5-benzyloxy-2-iodo-benzyl ester with 2-tert-butoxycarbonylamino-acrylicacid methyl ester in 74% yield. MS (ESI) 456 (M+H); R_(f)=1.87.

3-(2-Acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester. To a solution of3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-acrylicacid methyl ester (1.9 g, 4.2 mmol) in anhydrous methanol under nitrogenatmosphere was added1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I) trifluoromethanesulfonate (50 mg) and stirred on a Parr shaker at 50psi of hydrogen atmosphere for 18 h. The solvent was evaporated and thedesired product was crystallized from ethyl acetate-hexane in 90% yield.MS (ESI) 458 (M+H); R_(f)=1.81.

(8-Benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamicacid tert-butyl ester. To a solution of3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester (1.85 g, 4.0 mmol) in methanol (40 mL) was addedpotassium carbonate (560 mg, 4.0 mmol) at room temperature and stirredfor 1 h. The reaction mixture was diluted with dichloromethane (150 mL),washed with 1.0 M aqueous hydrogen chloride and dried (Na₂SO₄) to givethe pure3-(4-benzyloxy-2-hydroxymethyl-phenyl)-2-tert-butoxycarbonylamino-propionicacid methyl ester in almost quantitative yield. To the alcohol (800 mg,1.93 mmol) in dichloromethane (50 mL) was added methanesulfonyl chloride(0.18 mL, 2.3 mmol) followed by triethylamine (0.38 mL, 2.70 mmol) at 0°C. and then brought to room temperature. After 1 h, the reaction mixturewas washed with aqueous sodium hydrogencarbonate, dried (Na₂SO₄). Thesolvent was removed, dissolved the crude product in anhydrous THF (20mL) followed by addition of 2.0 M solution of methylamine in THF (10 mL)in a sealed tube. The sealed tube was heated at 80° C. for a period of12 h and then removed the solvent. The crude product was purified byflash chromatography using 30% ethyl acetate in hexane to give(8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamicacid tert-butyl ester in 39% overall yield. ¹H NMR (500 MHz, CDCl₃): inδ 7.40-7.31 (m, 5 H), 7.01-7.00 (m, 1 H), 6.83-6.82 (m, 1 H), 6.66 (s, 1H), 5.91-5.90 (m, 1 H), 5.13-5.01 (m, 4 H), 3.50-3.46 (m, 1 H), 3.03 (s,3 H), 2.85-2.78 (m, 1 H), 1.45 (s, 9 H).

Acetic acid 3-tert-butoxycarbonylamino-6-iodo-2-methyl-benzyl ester. Toa well stirred solution of 3-amino-2-methylbenzyl alcohol (10 g, 72.9mmol) in methanol (250 mL) was added a 1.0 M solution of iodinemonochloride in dichloromethane (76.6 mL) dropwise over a period of 5min at 0° C. The reaction mixture was then brought to room temperatureand stirring continued for additional 2 h. The reaction mixture was thenconcentrated, diluted with dichloromethane (250 mL), washed with 10%aqueous sodium thiosulphate and dried (Na2SO4). The solvent wasevaporated and the crude product was dissolved in THF (200 mL).Di-tert-butyl dicarbonate (15.9 g, 72.9 mmol) was added and the reactionmixture was refluxed for 48 h. The reaction mixture was then dilutedwith ether (400 mL) washed with 1 M HCl (2×100 mL) followed by brine anddried (Na2SO4). The solvent was removed and the desired product wascrystallized from 20% ethyl acetate in hexane to give(3-hydroxymethyl-4-iodo-2-methyl-phenyl)-carbamic acid tert-butyl ester(12.5 g). The filtrate was then concentrated and the desired product waspurified by flash chromatography (silica) using 30% ethyl acetate togive additional 2.5 g of(3-hydroxymethyl-4-iodo-2-methyl-phenyl)-carbamic acid tert-butyl ester.To a stirred solution of3-hydroxymethyl-4-iodo-2-methyl-phenyl)-carbamic acid tert-butyl ester(14.5 g, 40 mmol) in dichloromethane (150 mL) was added acetic anhydride(7.5 mL, 80 mmol) and catalytic amount of 4-dimethylaminopyridine andstirred for 12 h at room temperature. The reaction mixture was thenquenched with aqueous sodium hydrogencarbonate, brine and dried(Na₂SO₄). The solvent was removed and the crude product was purified bycrystallization from dichloromethane and hexane to give acetic acid3-tert-butoxycarbonylamino-6-iodo-2-methyl-benzyl ester (15.5 g, 94%).¹H NMR (500 MHz, CDCl₃): in δ 7.71 (d, J=8.5 Hz, 1 H), 7.25 (d, J=8.5Hz, 1 H), 5.30 (s, 2 H), 2.28 (s, 3 H), 2.08 (s, 3 H), 1.50 (s, 9 H); MS(ESI) 428 (M+Na); R_(f)=1.59.

3-(2-Acetoxymethyl-4-acetylamino-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester. In a manner similar to2-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzylidene)-succinicacid diethyl ester,3-(2-acetoxymethyl-4-acetylamino-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester was prepared by reacting acetic acid3-acetylamino-6-iodo-2,4-dimethyl-benzyl ester with2-benzyloxycarbonylamino-acrylic acid methyl ester in 74% yield. MS(ESI) 491 (M+H); R_(f)=1.87.

3-(2-Acetoxymethyl-4-acetylamino-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-propionicacid methyl ester. In a manner similar to3-(2-acetoxymethyl-4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-acrylicacid methyl ester,3-(2-acetoxymethyl-4-acetylamino-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-propionicacid methyl ester was prepared from3-(2-acetoxymethyl-4-acetylamino-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester (1.5 g) using1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I) trifluoromethanesulfonate (25 mg) in 98% yield. MS (ESI) 491 (M+H);R_(f)=1.87.

(8-Acetylamino-2,7,9-trimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamicacid benzyl ester. In a manner similar to2-(R)-benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionicacid methyl ester hydrochloride, the title compound was prepared byhydrolyzing3-(2-acetoxymethyl-4-acetylamino-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-propionicacid methyl ester (1.84 g, 3.78 mmol) with potassium carbonate (525 mg,3.8 mmol) in MeOH (40 mL). The alcohol was dissolved in dichloromethane(100 mL) and then treated with methanesulfonyl chloride (0.35 mL, 4.5mmol) and triethylamine (0.68 mL, 4.9 mmol). The reaction mixture wasstirred for 12 h, washed with aqueous sodium hydrogencarbonate, 1.0 Maqueous hydrogen chloride and dried (Na₂SO₄). The solvent was removed togive pure3-(4-acetylamino-2-chloromethyl-3,5-dimethyl-phenyl)-2-benzyloxycarbonylamino-propionicacid methyl ester in almost quantitative yield. The chloride (480 mg,1.08 mmol) was treated with 1.0 M methylamine solution in THF in asealed tube for 3 h at 90° C. The solvent was removed and the crudeproduct was dissolved in toluene and acetic acid (0.5 mL) and refluxedfor 2 h to give(8-acetylamino-2,7,9-trimethyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamic acid benzyl ester in 68% yield. To theacetate in chloroform (20 mL) was added acetic acid (0.5 mL) followed byisoamylnitrite (1.0 mL) and 18-crown-6 (50 mg). The reaction mixture wasrefluxed for 12 h and removed the solvent. The crude product waspurified by flash chromatography using ethyl acetate as eluent to give(4,9-dimethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester as a major product in 37% overall yield. ¹H NMR (500MHz, CDCl₃): in δ 7.96 (s, 1 H), 7.35-7.24 (m, 5 H), 6.7 (s, 1 H),6.43-6.41 (m, 1 H), 5.25-5.05 (m, 3 H), 4.18-4.10 (m, 2 H), 3.07-3.05(m, 2 H), 3.00)s, 3 H), 2.40 (s, 3 H).

(9-Isobutyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden7-yl)-carbamic acid benzyl ester. In a manner similar to[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester, the title compound was prepared by treating2-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester, hydrochloride with isobutylamine followed bytreatment with acetic acid in refluxing toluene to give(9-Isobutyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester in 91% yield. MS (ESI) 407 (M+H); R_(f)=1.58.

(8-Oxo-9-pyridin-4-ylmethyl-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester. In a manner similar to[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester, the title compound was prepared by treating2-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester, hydrochloride with 4-(aminomethyl)pyridine followedby treatment with acetic acid in refluxing toluene to give(8-oxo-9-pyridin-4-ylmethyl-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester in 65% yield. MS (ESI) 442 (M+H); R_(f)=1.10.

4-Iodo-2-methyl-3-nitrobenzenamine. To a well stirred solution of2-methyl-3-nitroaniline (10 g, 66 mmol) in methanol (150 mL) was addedsodium hydrogencarbonate (264 mmol) followed by 1.0 M solution of iodinemonochloride (72 mmol) at room temperature. After stirring for 1 h, thesolvent was removed, diluted with ether, washed with 10% aqueous sodiumthiosulfate solution. The solvent was removed and the crude iodide wasin the next step.

(E)-Diethyl 2-(4-amino-3-methyl-2-nitrobenzylidene)succinate. To asolution of 4-iodo-2-methyl-3-nitrobenzenamine (59 mmol) indimethylformamide (100 mL) was added diethyl itaconate (13.2 g, 71mmol), tetrabutylammonium chloride (16.4 g, 59 mmol), triethylamine (236mmol) and palladium acetate (675 mg, 3 mmol) under nitrogen. Thereaction mixture was heated to 80° C. for 2 h. The crude reactionmixture was then filtered, diluted with ether (250 mL), washed withwater (2×300 mL). The crude product was purified by flash chromatographyusing 20% ethyl acetate in hexane to give 8.5 g of the title compound.¹H NMR (500 MHz, CDCl₃): in δ 7.58 (s, 1 H), 7.10 (d, J=8.5 Hz, 1 H),6.73 (d, J=8.5 Hz, 1 H), 4.24-4.15 (m, 4H), 3.40 (s, 2 H), 2.06 (s, 3H), 1.30-1.23 (m, 6 H).

Ethyl2-(7-amino-8-methyl-1-neopentyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate.To a solution of (E)-diethyl2-(4-amino-3-methyl-2-nitrobenzylidene)succinate (4.5 g, 13.4 mmol) inTHF (100 mL) was added (Boc)₂O (16 mmol) followed by catalytic amount ofdimethylaminopyridine (10 mg). The reaction mixture was heated in asealed tube for 3 h at 100° C. The reaction mixture was cooled, removedsolvent, diluted with ether and then washed with aqueous sodiumhydrogencarbonate (50 mL). The crude product was found to contain bothmono- and di-Boc protected compounds. The crude product was dissolved inmethanol (200 mL) and was added water (150 ml) followed by ammoniumchloride (14.3 g, 268 mmol) and iron powder (8.9 g, 160 mmol). Thereaction mixture was heated at 50° C. for 1 h, cooled and then filteredover a pad of celite. The solvent was removed, extracted with ethylacetate and then washed with brine and dried (Na₂SO₄). The crude productwas purified by flash chromatography using 30% ethyl acetate in hexaneas eluent to give the amine. The amine (4.1 g, 10 mmol) was dissolved indichloroethane (100 mL) followed by addition of acetic acid (10 mL),trimethylacetaldehyde (11 mmol) and magnesium sulfate (5.0 g). Thereaction mixture was stirred for 2 h and then filtered. To the filteredreaction mixture was added sodium triacetoxyborohydride (2.33 g, 11mmol) and stirring continued for additional 2 h. The reaction mixturewas diluted with hexane (150 mL), washed with water (2×100 mL), aqueousNaHCO₃ solution and dried (Na₂SO₄). The solvent was removed and thecrude product was dissolved in methanol (100 mL) followed by addition ofacetic acid (5 mL) and hydrogenated in a parr bottle at a pressure of 50psi hydrogen. The catalyst was removed by filtration and the solvent wasremoved. The crude product was dissolved in toluene (100 mL) followed byaddition of tosic acid (100 mg) and sodium cyanide (50 mg). The reactionmixture was refluxed for 12 h and the crude product was purified byflash chromatography using 50% ethyl acetate in hexane to give ethyl2-(7-amino-8-methyl-1-neopentyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate.

MS (ESI) 333 (M+H); R_(f)=1.29.

2-(1-Neopentyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[3,4-h]quinolin-3-yl)aceticacid. To a solution of ethyl2-(7-amino-8-methyl-1-neopentyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate(170 mg, 0.51 mmol) in carbon tetrachloride (4.5 mL) was added aceticacid (0.5 mL) followed by isoamylnitrite (0.04 mL) and the reactionmixture was stirred for 2 h at room temperature. The reaction mixturewas diluted with dichloromethane (40 mL), washed with aqueous NaHCO₃ anddried. The solvent was removed and the crude product was dissolved inTHF (15 mL) followed by addition of lithium hydroxide (43 mg, 1 mmol)and water (5 mL). After stirring for 12 h, the solvent was removed,acidified with 6 M HCl and extracted with ethyl acetate to give2-(1-neopentyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[3,4-h]quinolin-3-yl)aceticacid.

MS (ESI) 316 (M+H); R_(f)=1.31.

2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic aciddiethyl ester. 2-(S)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinicacid diethyl ester (3.0 g, 8.2 mmol) was dissolved in acetonitrile (40mL). Mixture was warmed to 60° C. N-Chlorosuccinimide (1.29 g, 9.7 mmol)was added to the warm solution. Reaction mixture was heated at refluxfor 10 minutes. Mixture was cooled to room temperature then diluted withethyl acetate (20 mL). Mixture was washed successively with saturatedaqueous sodium bicarbonate (40 mL), and brine (20 mL). Organic was dried(magnesium sulfate), filtered and concentrated in vacuo. Silica gelchromatography (ethyl acetate-hexanes) afforded the desired product in59% yield as an amber oil. ¹H NMR (300 MHz, CDCl₃): δ=6.98 (s, 1H), 5.15(d, J=3.3, 2H), 4.09 (m, 4H), 2.99 (m, 2H), 2.69 (m, 2H), 2.39 (dd,J1=4.8, J2=16.5, 1H), 2.17 (s, 3H), 2.06 (s, 3H), 1.20 (m, 6H). MS m/e(M−C₂H₄O₂+H)⁺=340.0.

2-(S)-(4-Acetoxymethyl-7-chloro-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester. Isoamyl nitrite (700 μL, 5.2 mmol), was added dropwise toan ice cold solution of2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic aciddiethyl ester (1.91 g, 4.8 mmol) in 5% acetic acid in tolune (81.2 mL).Mixture stirred at 0° C. for 45 minutes. Potassium acetate (1.50 g, 15.3mmol) was added to the mixture. Reaction was stirred at room temperaturefor 14 hours. Mixture was quenched with water. Mixture was extractedwith ethyl acetate (30 mL). Mixture was washed 2× saturated aqueoussodium bicarbonate. Organic was dried (magnesium sulfate) filtered andconcentrated. Silica gel chromatography (ethyl acetate-hexanes) affordedthe desired product in 80% yield as an amber oil. ¹H NMR (300 MHz,CDCl₃): δ=8.23 (s, 1H), 7.26 (s, 1H), 5.45 (s, 2H), 4.09 (q, J=7.0, 4H),3.20 (dd, J1=7.32, J2=13.2, 1H), 3.10 (m, 1H), 2.97 (dd, J1=7.0,J2=13.3, 1H), 2.73 (dd, J1=8.4, J2=16.8, 1H), 2.44 (dd, J1=5.5, J2=16.8,1H), 2.08 (s, 3H), 1.18 (m, 6H). MS m/e (M+H)⁺=411.0.

(S)-Dimethyl2-((7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate.2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic aciddiethyl ester (2.21 g, 5.4 mmol) was converted to the title compound ina manner analogous to the preparation of2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester. Material was obtained as amber solid in 99% yield. MS m/e(M+H)⁺=241.2.

(S)-Dimethyl2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate.(S)-Dimethyl2-((7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (2.0 g,5.9 mmol) was dissolved in dichloromethane (35 mL). Thionyl chloride(5.0 mL) was added to the mixture. Reaction stirred at room temperaturefor 1.5 hours. Mixture was concentrated. Residue was dissolved in ethylacetate. Mixture was washed twice with aqueous sodium bicarbonate andonce with brine. Organic was dried (magnesium sulfate), filtered andconcentrated in vacuo. Title compound was obtained as amber solid in 89%yield. MS m/e (M+H)⁺=359.1.

(S)-Methyl 2-(4-chloro-8-oxo-9-(pyridin-4-ylmethyl)-36,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate. (S)-Dimethyl2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (120 mg,0.33 mmol) was dissolved in DMF (1.0 mL). 4-Aminomethylpyridine (100 μL,1.0 mmol) was added to the mixture. Reaction stirred at room temperaturefor 24 hours. Mixture was diluted with ethyl acetate. Mixture was washedtwice with water and once with brine. Organic was dried (magnesiumsulfate), filtered and concentrated in vacuo. Residue was dissolved intoluene (4 mL). Acetic acid (1 mL) was added to the mixture. Reactionwas heated at reflux for 3.5 hours. Mixture was cooled to roomtemperature then diluted with ethyl acetate. Material was washed oncewith water and twice with aqueous sodium bicarbonate. Aqueous was madebasic with sodium bicarbonate. Back extracted from the aqueous twicewith ethyl acetate. Combined organics were dried (magnesium sulfate),filtered and concentrated in vacuo. Residue was purified with silica gelchromatography eluting dichloromethane and 2N ammonia in methanol. Titlecompound was obtained as yellow solid in 48% yield. MS m/e (M+H)⁺=399.2.

(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid dihydrochloride. (S)-Methyl2-(4-chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate(21 mg, 0.05 mmol) was dissolved in 1N hydrochloric acid (1.0 mL).Reaction was heated at 50° C. for 5 hours. Another 1 mL of 1Nhydrochloric acid was added to the mixture. Reaction was heated at 50°C. for 17 hours. Mixture was concentrated in vacuo. Residue was treatedwith acetonitrile and then the material was concentrated. Title compoundwas obtained as dark yellow solid in 83% yield. MS m/e (M+H)⁺=385.2.

(S)-Methyl2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate.(S)-Dimethyl2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (250 mg,0.63 mmol) and (1H-imidazol-2-yl)methanamine dihydrochloride (170 mg,1.0 mmol) were combined and suspended in acetonitrile (10 mL).Triethylamine (800 μL, 5.7 mmol) was added to the mixture. Reaction waswarmed to reflux for 3 hours. Acetic acid (1.5 mL) was added to themixture. Reaction was heated at reflux for 20 hours. Mixture was cooledto room temperature then diluted with dichloromethane. Mixture wasextracted twice with water. Aqueous layer was concentrated in vacuo.Residue was purified by preparatory HPLC. Water was lyophilized off.Remaining residue was passed through a column of Dowex 1×4-200 ionexchange resin eluting methanol. Title compound was recovered as amberresidue in 24% yield. MS m/e (M+H)⁺=388.1.

5-Amino-2-iodo-4-methybenzyl alcohol. To an ice cooled solution of3-amino-4-methylbenzyl alcohol (10.0 g, 72.9 mmol) in methanol (200 mL)1M iodinemonochloride in dichloromethane (80.0 mL, 80.0 mmoles) wasadded drop-wise over 30 minutes. Ice bath was removed. Reaction wasstirred at ambient temperature for 40 minutes. Mixture was concentratedin vacuo. Residue was treated with dichloromethane (250 mL). Solids werefiltered off and washed with dichloromethane. Solids were partitionedbetween ethyl acetate and 1N aqueous sodium hydroxide. Layers werepartitioned. Organic layer was washed with 1N aqueous sodium hydroxide.The combined aqueous layers were back extracted two times with ethylacetate. Combined organic layers were washed with brine. Combinedextracts were dried (magnesium sulfate), filtered and concentrated invacuo. Desired product was obtained as tan solid in 81% yield. MS m/e(M+H)⁺=264.

tert-Butyl 5-(hydroxymethyl)-4-iodo-2-methylphenylcarbamate.5-Amino-2-iodo-4-methybenzyl alcohol (4.60 g, 17.5 mmoles) was dissolvedin tetrahydrofuran (80 mL). Di-tert-butyl dicarbonate (5.30 g, 24.3mmoles) was added to the mixture. Reaction was heated at 60° C. for 20hours. Mixture was concentrated. Residue was purified by silica gelchromatography eluting ethyl acetate-hexanes. Title compound wasobtained as off-white solid. MS m/e (M−C₄H₈O+H)⁺=290.

5-(tert-Butoxycarbonyl)-2-iodo-4-methylbenzyl acetate. tert-Butyl5-(hydroxymethyl)-4-iodo-2-methylphenylcarbamate (4.32 g, 11.9 mmol) wasdissolved in dichloromethane (60 mL). Acetic anhydride (2.6 mL, 27.6mmol) was added to the mixture followed by potassium acetate (2.0 g,20.4 mmol). Reaction was stirred at room temperature over 15 hours.Mixture was warmed to 50° C. and held for 1 hour. Mixture was cooled toroom temperature then diluted with dichloromethane. Mixture was washedtwice with water, and once with saturated aqueous sodium bicarbonate.Organic layer was dried (magnesium sulfate), filtered and concentratedin vacuo. Residue was treated with 10% ethyl acetate-hexanes (100 mL).Material was concentrated in vacuo. Desired compound was obtained aswhite solid in 98% yield. ¹H NMR (300 MHz, CD₃OD): δ=7.64 (s, 1H), 7.54(s, 1H), 4.51 (s, 2H), 2.19 (s, 3H), 1.51 (s, 9H).

3-(2-Acetoxymethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester. Title compound was prepared in a manner analogous tothe preparation of3-(2-Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-benzyloxycarbonylamino-acrylicacid methyl ester. Material was obtained as a white solid in 65% yield.MS m/e (M+H)⁺=513.

3-(2-Acetoxymethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester. Title compound was prepared in a manner analogous tothe preparation of2-(S)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester. Material was obtained as clear colorless oil in 99%yield. MS m/e (M−H)⁻=513.

3-(2-Hydroxymethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester. Title compound was obtained in a manner analogous tothe preparation of2-(R)-Benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionicacid methyl ester. Material was obtained as white solid in 94% yield.

3-(2-Chloromethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester.3-(2-Hydroxymethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester (510 mg, 1.1 mmol) was dissolved in dichloromethane (5mL). Triethylamine (250 μL, 1.8 mmol ) was added to the mixture followedby methanesulfonyl chloride (100 μL, 1.3 mmol). Mixture was stirred atroom temperature for 1.5 hours. Mixture was diluted with dichloromethanethen washed once with water, twice with 1N hydrochloric acid, and oncewith brine. Organics were dried (magnesium sulfate), filtered andconcentrated in vacuo. Title compound was obtained as white solid in 91%yield. MS m/e (M+H)⁺=491.

(R)-Benzyl8-tert-butoxycarbonylamido-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-ylcarbamate.3-(2-Chloromethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester (335 mg, 0.72 mmol) was dissolved in acetonitrile (10mL). Potassium carbonate (220 mg, 1.6 mmol) was added to the mixturefollowed by benzylamine (150 μL, 1.4 mmol). Reaction was heated toreflux for 4.5 hours. Mixture was cooled to room temperature. Mixturewas filtered over celite. Filtrate was concentrated. Residue wasdissolved in toluene (15 mL). Acetic acid (100 μL) was added to themixture. Reaction was heated at reflux for 3 hours. Mixture was cooledto room temperature. Mixture was concentrated. Residue was purified bysilica gel chromatography eluting ethyl acetate-hexanes. Title compoundwas obtained as clear colorless oil in 81% yield. MS m/e (M+H)⁺=530.

(R)-tert-Butyl4-amino-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate.(R)-Benzyl8-tert-butoxycarbonylamido-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-ylcarbamate(305 mg, 0.58 mmol) was dissolved in methanol. A catalytic amount of 10%palladium on carbon was added to the mixture. Reaction was placed on aParr apparatus under 50 psi of hydrogen gas. Reaction shook at roomtemperature for 1 hour. Reaction was removed from the apparatus.Catalyst was filtered off. Filtrate was concentrated in vacuo. Titlecompound was obtained as clear colorless oil in 97% yield. MS m/e(M+H)⁺=396.

(R)-tert-Butyl2-benzyl-7-methyl-3-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamido)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate.(R)-tert-Butyl4-amino-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate(155 mg, 0.39 mmol) was dissolved in dichloromethane (10 mL). Aqueoussodium bicarbonate (10 mL) was added to the mixture. A solution of 20%phosgene in toluene (230 μL, 0.43 mmol) was added to the mixture withvigorous stirring. Reaction stirred at room temperature for 20 minutes.4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine acetate (140 mg,0.48 mmol) was added to the mixture. Reaction stirred at roomtemperature for 1 hour. Reaction layers were partitioned. Organic layerwas washed successively with 1N hydrochloric acid and brine. Organic wasdried (magnesium sulfate), filtered and concentrated in vacuo. Titlecompound was obtained as off-white solid in 94% yield. MS m/e(M+H)⁺=653.

(R)-Benzyl8-tert-butoxycarbonylamido-2-benzyl-9-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-ylcarbamate.3-(2-Chloromethyl-4-tert-butoxycarbonylamino-3-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester was reacted in a manner analogous to the preparationof (R)-benzyl8-tert-butoxycarbonylamido-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-ylcarbamate.Title compound was obtained as white solid in 78% yield. MS m/e(M+H)⁺=530.

(R)-tert-Butyl4-amino-2-benzyl-9-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate.(R)-Benzyl8-tert-butoxycarbonylamido-2-benzyl-9-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-ylcarbamatewas reacted in a manner analogous to the preparation of (R)-tert-butyl4-amino-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate.Title compound was obtained as clear colorless oil in 99% yield. MS m/e(M+H)⁺=340.

(R)-Benzyl1-acetyl-8-benzyl-7-oxo-1,5,6,7,8,9-hexahydroazepino[4,3-f]indazol-6-ylcarbamate.3-(2-Chloromethyl-4-tert-butoxycarbonylamino-5-methyl-phenyl)-2-(R)-benzyloxycarbonylamino-propionicacid methyl ester (160 mg, 0.33 mmol) was dissolved in dichloromethane(3 mL). Trifluoroacetic acid (1 mL) was added to the mixture. Reactionwas stirred at room temperature for 45 minutes. Mixture was concentratedto a yellow oil. Residue was dissolved in chloroform (3 mL). Acetic acid(100 μL) was added to the mixture followed by isoamyl nitrite (50 μL,0.37 mmol) then potassium acetate (65 mg, 0.66 mmol). Reaction washeated at reflux for 30 minutes. Mixture was cooled to room temperaturethen diluted with dichloromethane. Mixture was washed once with water,and twice with aqueous sodium bicarbonate. Organics were dried(magnesium sulfate), filtered and concentrated in vacuo. Reside wasdissolved in acetonitrile (3 mL). Benzylamine (100 μL, 0.92 mmol) wasadded to the mixture followed by potassium carbonate (50 mg, 0.36 mmol).Reaction was heated at reflux for 1 hour. Mixture was cooled to roomtemperature. Solids were filtered. Filtrate was concentrated in vacuo.Residue was treated with toluene (3 mL) and acetic acid (100 μL).Reaction was heated at reflux for 1 hour. Mixture was cooled to roomtemperature. Acetic anhydride (1 mL) was added to the mixture. Reactionwas stirred at room temperature for 1 hour. Mixture was concentrated.Residue was purified by silica gel chromatography eluting ethylacetate-hexanes. Title compound was obtained as amber oil in 27% yield.MS m/e (M+H)⁺=483.

(R)-benzyl8-oxo-9-(piperidin-4-yl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamatemethanesulfonate.4-(7-(R)-Benzyloxycarbonylamino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylicacid tert-butyl ester (100 mg, 0.19 mmol) was dissolved indichloromethane (2 mL). Anisole (100 μL, 0.92 mmol) was added to themixture followed by methanesulfonic acid (200 μL). Reaction stirred atroom temperature for 30 minutes. Mixture was diluted with diethyl ether,and the mixture stirred at room temperature for 30 minutes. Solventswere decanted off. Residue was dried in vacuo. Title compound wasobtained as dark oil in quantitative yield. MS m/e (M+H)⁺=434.

(R)-benzyl9-(1-acetylpiperidin-4-yl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate.(R)-benzyl8-oxo-9-(piperidin-4-yl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamatemethanesulfonate (100 mg, 0.19 mmol) was dissolved in a mixture ofdichloromethane (4 mL) and triethylamine (500 μL, 3.6 mmol). Aceticanhydride (500 μL, 5.3 mmol) was added to the mixture. Reaction stirredat room temperature overnight. Reaction mixture was washed successively1× water, 2× 1N hydrochloric acid, 2× 1N sodium hydroxide, and 1× brine.Organic was dried (magnesium sulfate), and filtered. Filtrate wasconcentrated in vacuo. Residue was treated with methanol (3 mL).Potassium carbonate (40 mg, 0.29 mmol) was added to the mixture.Reaction stirred at room temperature for 2 hours. Reaction was quenchedwith 1N hydrochloric acid (6 mL). Methanol was removed from the mixturein vacuo. Remaining aqueous mixture was made basic with sodiumbicarbonate. Mixture was extracted with ethyl acetate. Organic layer wasdried (magnesium sulfate), filtered and concentrated. Title compound wasobtained as yellow solid in 43% yield. MS m/e (M+H)⁺=476.

(R)-9-(]-acetylpiperidin-4-yl)-7-amino-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-onemethanesulfonate. (R)-benzyl9-(1-acetylpiperidin-4-yl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate(38 mg, 0.08 mmol) was dissolved in dichloromethane (1 mL). Anisole (30μL, 0.27 mmol) was added to the mixture followed by methanesulfonic acid(250 μL). Reaction stirred at room temperature for 2 hours. Mixture wasdiluted with diethyl ether. Mixture sat at room temperature for 30minutes. Solvents were decanted off. Remaining residue was dried invacuo. Title compound was obtained as dark oil in quantitative yield. MSm/e (M+H)⁺=342.

tert-butyl3-((R)-7-(benzyloxycarbonyl)-8-oxo-7,8-dihydroazepino[3,4-e]indazol-9(3H,6H, 10H)-yl)pyrrolidine-1-carboxylate.2-(R)-Benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionicacid methyl ester hydrochloride (150 mg, 0.31 mmol) andR,S-3-amino-1-N-Boc-pyrrolidine (90 μL, 0.48 mmol) were reacted in amanner analogous to the preparation of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Title compound was obtained without purification asdark foam in 96% yield. MS m/e (M+H)⁺=342.

3-(tert-butoxycarbonyl)-2-methyl-6-((2-oxo-2,5-dihydrofuran-3-yl)methyl)benzylacetate. Acetic acid 3-tert-butoxycarbonylamino-6-iodo-2-methyl-benzylester (575 mg, 1.4 mmol) was dissolved in N,N-dimethylformamide (2.5mL). α-Methylene-γ-butyrolactone (190 μL, 2.2 mmol) was added to themixture followed by potassium acetate (420 mg, 4.3 mmol), and thenpalladium(II)acetate (16 mg, 0.07 mmol). Reaction mixture was heated at80° C. for 26 hours. Mixture was cooled to room temperature andpartitioned between ethyl acetate and aqueous sodium bicarbonate. Layerswere separated. Organic layer was dried (magnesium sulfate), filteredand concentrated in vacuo. Silica gel chromatography afforded the titlecompound as off-white solid in 54% yield. MS m/e (M−H)⁻=374.

(S)-3-(tert-butoxycarbonyl)-2-methyl-6-((2-oxo-tetrahydrofuran-3-yl)methyl)benzylacetate.3-(tert-butoxycarbonyl)-2-methyl-6-((2-oxo-2,5-dihydrofuran-3-yl)methyl)benzylacetate (280 mg, 0.75 mmol) was dissolved in a mixture of ethyl acetate(10 mL) and methanol (10 mL). A catalytic amount of(−)-1,2-bis((2R,5R)-diethylphospholano)benzene(cyclooctadiene)rhodium(I)tetrafluoroboratewas added to the mixture. Reaction vessel was placed on a Parr apparatusand charged with 50 psi of hydrogen gas. Reaction shook at roomtemperature for 16 hours. A fresh portion of(−)-1,2-bis((2R,5R)-diethylphospholano)benzene(cyclooctadiene)rhodium(I)tetrafluoroboratewas added to the mixture. Reaction vessel was charged with 50 psi ofhydrogen gas. Reaction shook at room temperature for 24 hours. Reactionmixture was concentrated in vacuo. Residue was passed through a plug ofsilica gel eluting 80% ethyl acetate-hexanes. Filtrate was concentratedin vacuo. Title compound was obtained as clear colorless oil in 69%yield. MS m/e (M−H)⁻=376.

(S)-3-((4-(hydroxymethyl)-1H-indazol-5-yl)methyl)-dihydrofuran-2(3H)-one.(S)-3-(tert-butoxycarbonyl)-2-methyl-6-((2-oxo-tetrahydrofuran-3-yl)methyl)benzylacetate (190 mg, 0.50 mmol) was dissolved in dichloromethane (4 mL).Trifluoroacetic acid (1 mL) was added to the mixture. Reaction stirredat room temperature for 30 minutes. Mixture was diluted withdichloromethane and then concentrated in vacuo. Residue was dissolved inchloroform (5 mL). Acetic acid (250 μL) was added to the mixturefollowed by isoamyl nitrite (80 μL, 0.60 mmol). Reaction stirred at roomtemperature for 20 minutes. Potassium acetate (400 mg, 4.1 mmol) wasadded to the mixture. Reaction stirred at room temperature for 1 hour.Mixture was diluted with dichloromethane. Mixture was washedsuccessively 1× water, 2× aqueous sodium bicarbonate. Organic layer wasdried (magnesium sulfate), filtered and concentrated in vacuo. Residuewas dissolved in methanol (5 mL). Potassium carbonate (120 mg, 0.87mmol) was added to the mixture. Reaction stirred at room temperature for1 hour. Reaction was quenched with 1N hydrochloric acid. Methanol wasremoved from the mixture in vacuo. Remaining aqueous was extracted 2×diethyl ether, made basic with sodium bicarbonate, and then extractedagain 2× diethyl ether. Combined extracts were dried (magnesiumsulfate), filtered, and concentrated in vacuo. Title compound wasobtained as amber oil in 73% yield. MS m/e (M+H)⁺=247.

(S)-2-(9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)ethylacetate.(S)-3-((4-(hydroxymethyl)-1H-indazol-5-yl)methyl)-dihydrofuran-2(3H)-one(70 mg, 0.28 mmol), was dissolved in dichloromethane (1.5 mL). Thionylchloride (500 μL) was added to the mixture. Reaction stirred at roomtemperature for 45 minutes. Mixture was concentrated. Residue wastreated with dichloromethane and re-concentrated. Residue was dissolvedin acetonitrile (3 mL). Potassium carbonate (150 mg, 1.1 mmol) was addedto the mixture followed by neopentylamine (100 μL, 0.85 mmol). Mixturewas heated at reflux for 45 minutes. Mixture was cooled to roomtemperature and filtered. Filtrate was concentrated in vacuo. Residuewas dissolved in toluene (5 mL). Acetic acid (200 μL) was added to themixture. Reaction was heated at reflux for 5.5 hours. Mixture wasconcentrated in vacuo. Preparatory HPLC purification gave the titlecompound as yellow solid in 19% yield. MS m/e (M−H)⁻=356.

(S)-7-(2-hydroxyethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(S)-2-(9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)ethylacetate (18 mg, 0.05 mmol) was dissolved in methanol (1 mL). Potassiumcarbonate (20 mg, 0.14 mmol) was added to the mixture. Reaction stirredat room temperature for 1 hour. Amberlite IRC-50 ion exchange resin wasadded to the mixture. Reaction stirred at room temperature for 15minutes. Mixture was filtered. Filtrate was concentrated in vacuo. Thetitle compound was obtained as yellow residue in 94% yield. MS m/e(M+H)⁺=316.

2-(R)-(Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester.2-(S)-(Acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzylidene)-succinicacid diethyl ester (700 mg, 1.5 mmol) was hydrogenated in a manneranalogous to the preparation of2-(S)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester using(+)-1,2-bis((2S,5S)-diethylphospholano)benzene(cyclooctadiene)rhodium(I)trifluoromethanesulfonate as the catalyst. Silica gel chromatography afforded the titlecompound as lightly colored oil in 75% yield. MS m/e (M−H)⁻=464.0.

2-(R)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethylester. Trifluoroacetic acid (2.5 mL) was added to a solution of2-(R)-(acetoxymethyl-4-tert-butoxycarbonylamino-3-methyl-benzyl)-succinicacid diethyl ester (525 mg, 1.1 mmol) in dichloromethane (10 mL).Reaction mixture was stirred at room temperature for 1 hour. Mixture wasconcentrated in vacuo. Residue was treated with aqueous sodiumbicarbonate and extracted with ethyl acetate (2×20 mL). Combined organiclayers were dried (magnesium sulfate), filtered and concentrated invacuo. The title compound was obtained as amber oil in 99% yield. MS m/e(M-C₂H₄O₂+H)⁺=306.1.

2-(R)-(4-Acetoxymethyl-1H-indazol-5-ylmethyl)-succinic acid diethylester. Isoamyl nitrite (170 μL, 1.3 mmol) was added dropwise to a cooled(water ice bath) solution of2-(R)-(2-acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethylester in 5% acetic acid—chloroform (5 mL). Mixture was stirred at 0° C.for 1.5 hours. Mixture was diluted with dichloromethane (20 mL) and thenwashed with saturated aqueous sodium bicarbonate (2×20 mL). Organic wasdried (magnesium sulfate), filtered and concentrated in vacuo. Titlecompound was obtained as amber oil in 99% yield. MS m/e (M+H)⁺=377.1.

2-(R)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester. Potassium carbonate (380 mg, 2.7 mmol) was added to a solution of2-(R)-(4-acetoxymethyl-1H-indazol-5-ylmethyl)-succinic acid diethylester (420 mg, 1.1 mmol) in methanol (10 mL). Mixture was stirred atroom temperature for 2 hours. Reaction was quenched with 1N hydrochloricacid. Methanol was removed from the mixture in vacuo. Remaining aqueousmade basic with sodium bicarbonate. Mixture was extracted with ethylacetate (2×20 mL). Combined organic layers were washed successively withwater (20 mL) and brine (20 mL). Organic was dried (magnesium sulfate),filtered and concentrated in vacuo. Title compound was obtained as amberoil in 92% yield. MS m/e (M+H)⁺=307.1.

[9-(2,2-Dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Thionyl chloride (2 mL) was added to a solution of2-(R)-(4-hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester (280 mg, 0.91 mmol) in dichloromethane (4 mL). Reaction wasstirred at room temperature for 1 hour. Mixture was diluted withdichloromethane and then concentrated in vacuo. Residue was suspended inacetonitrile (5 mL). Potassium carbonate (300 mg, 2.2 mmol) was added tothe mixture followed by neopentylamine (250 μL, 2.1 mmol). Reaction washeated at reflux for 30 minutes. Neopentylamine (150 μL, 1.3 mmol) wasadded to the mixture. Reaction was heated at reflux for 20 minutes.Mixture was cooled to room temperature and filtered. Filtrate wasconcentrated in vacuo. Residue was dissolved in toluene (5 mL). Aceticacid (300 μL) was added to the mixture. Reaction was heated at refluxfor 16 hours. Mixture was cooled to room temperature and diluted withethyl acetate. Mixture was washed successively with aqueous sodiumbicarbonate (2×), water, and brine. Organic layer was dried (magnesiumsulfate), filtered and concentrated in vacuo. Silica gel chromatographyafforded the title compound as amber oil in 29% yield. MS m/e(M−H)⁻=342.1.

[9-(2,2-Dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-aceticacid. Lithium hydroxide monohydrate (31 mg, 0.74 mmol) was added to asolution of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (90 mg, 0.26 mmol) in methanol (2.5 mL),tetrahydrofuran (2 mL) and water (2.5 mL). Reaction mixture was heatedat 50° C. for 1.5 hours. The organic solvents were removed from themixture in vacuo. Remaining aqueous was neutralized with 1 Nhydrochloric acid (730 μL). Mixture was extracted with ethyl acetate(2×20 mL). Combined organic layers were washed with brine (20 mL) andthen dried (magnesium sulfate), filtered and concentrated in vacuo.Title compound was obtained as amber solid in 88% yield. MS m/e(M−H)⁻=328.1.

[4-Chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid. 2-(S)-(4-acetoxymethyl-7-chloro-1H-indazol-5-ylmethyl)-succinicacid diethyl ester (530 mg, 1.48 mmol) and 2,2,2-trifluoroethylamine (1mL, 12.5 mmol) was reacted following reaction scheme and proceduresanalogous to the preparation of[4-Chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as white solid in 20% yield. MS m/e(M−H)⁻=374.0.

2-(S)-(2-Acetoxymethyl-4-amino-5-bromo-3-methyl-benzyl)-succinic aciddiethyl ester. 2-(S)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinicacid diethyl ester (7.6 g, 21 mmol) was dissolved in acetic acid (100mL). Sodium acetate (4.2 g, 51 mmol) was added to the solution. Reactionvessel was placed in a cool water bath to control reaction exotherm.Bromine (1.1 mL, 22 mmol) was added to the mixture in one portion.Reaction stirred at ambient temperature for 10 minutes. Mixture waspoured into 1N aqueous sodium thiosulfate solution (400 mL). Materialwas extracted twice with ethyl acetate. Organic phase was washedsuccessively with water and brine. Organic was dried (magnesiumsulfate), filtered and concentrated in vacuo. Silica gel chromatography(ethyl acetate-hexanes) afforded the desired product in 77% yield as anamber oil. MS m/e (M−H)⁻=440.0, 442.0.

2-(S)-(4-Acetoxymethyl-7-bromo-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester. Isoamyl nitrite (2.3 mL, 17 mmol), was added drop-wise toan ice cold solution of2-(S)-(2-Acetoxymethyl-4-amino-5-bromo-3-methyl-benzyl)-succinic aciddiethyl ester (7.14 g, 16 mmol) in 5% acetic acid in toluene (280 mL).Mixture stirred at 0° C. for 40 minutes. Potassium acetate (4.00 g, 41mmol) was added to the mixture. Mixture was slowly warmed to roomtemperature. Reaction was stirred at room temperature for 14 hours.Mixture was washed twice with water and once with brine. Organic wasdried (magnesium sulfate) filtered and concentrated. Silica gelchromatography (ethyl acetate-hexanes) afforded the desired product in77% yield as an amber oil. MS m/e (M+H)⁺=455.0, 457.0.

(S)-dimethyl2-((7-bromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate.2-(S)-(2-Acetoxymethyl-4-amino-5-bromo-3-methyl-benzyl)-succinic aciddiethyl ester (2.78 g, 6.1 mmol) was converted to the title compound ina manner analogous to the preparation of2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester. Material was obtained as amber solid in 96% yield. MS m/e(M−H)⁻=383.0, 385.0.

(S)-dimethyl2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate.(S)-dimethyl2-((7-bromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (2.25 g,5.8 mmol) was dissolved in 2M thionyl chloride in dichloromethane (42mL, 84 mmol). Reaction stirred at room temperature for 2.0 hours.Mixture was concentrated. Residue was treated with toluene and thenconcentrated by roto-vap. Residue was dissolved in ethyl acetate.Mixture was washed twice with aqueous sodium bicarbonate. Organic wasdried (magnesium sulfate), filtered and concentrated in vacuo. Titlecompound was obtained as amber solid in 99% yield. MS m/e (M+H)⁺=404.9,403.0, 406.9

[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. (S)-dimethyl2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (860 mg,2.1 mmol) was dissolved in acetonitrile (50 mL). Potassium carbonate(625 mg, 4.5 mmol) was added to the mixture followed by neopentylamine(800 μL, 6.78 mmol). Mixture was heated to reflux and held with stirringfor 1.5 hours. Mixture was cooled to room temperature. Mixture wasfiltered over celite. Filtrate was concentrated by roto-vap. Residue wasdissolved in a mixture of toluene (50 mL) and acetic acid (3 mL).Mixture was heated to reflux and held with stirring for 37 hours.Mixture concentrated by roto-vap. Silica gel chromatography (ethylacetate-hexanes) afforded the title compound as tan solid in 75% yield.MS m/e (M−H)⁻=420.0, 422.0.

[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid.[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (160 mg, 0.38 mmol) was dissolved in a mixture oftetrahydrofuran (5.0 mL) and methanol (5.0 mL). Water (5.0 mL) was addedto the mixture followed by lithium hydroxide monohydrate (41 mg, 0.98mmol). Mixture was heated to 50° C. and held with stirring for 5 hours.Mixture was cooled to room temperature. Organic solvents were removedfrom the mixture in vacuo. Remaining aqueous was diluted with water andthen made neutral with 1 mL of 1N hydrochloric acid. Material wasextracted twice with ethyl acetate. Organic phase was dried (magnesiumsulfate), filtered and concentrated to dryness. Title compound wasobtained as tan solid in quantitative yield. ¹H NMR (300 MHz, CDCl₃)δ=0.77 (s, 9 H) 2.31-2.60 (m, 3 H) 2.91 (dd, J=16.47, 8.42 Hz, 1 H)2.98-3.05 (m, 1 H) 3.09 (d, J=13.54 Hz, 1 H) 3.47 (d, J=13.91 Hz, 1 H)3.71-3.89 (m, 1 H) 4.39 (d, J=17.20 Hz, 1 H) 5.30 (d, J=17.20 Hz, 1 H)7.25 (s, 1 H) 8.00 (s, 1 H).

[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. (S)-dimethyl2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (860 mg,2.1 mmol) was dissolved in acetonitrile (50 mL). Potassium carbonate(625 mg, 4.5 mmol) was added to the mixture followed by neopentylamine(800 μL, 6.78 mmol). Mixture was heated to reflux and held with stirringfor 1.5 hours. Mixture was cooled to room temperature. Mixture wasfiltered over celite. Filtrate was concentrated by roto-vap. Residue wasdissolved in a mixture of toluene (50 mL) and acetic acid (3 mL).Mixture was heated to reflux and held with stirring for 37 hours.Mixture concentrated by roto-vap. Silica gel chromatography (ethylacetate-hexanes) afforded the title compound as tan solid in 75% yield.MS m/e (M−H)⁻=420.0, 422.0.

[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester.2-(S)-(4-chloromethyl-7-bromo-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester (325 mg, 0.81 mmol) was dissolved in acetonitrile (10 mL).Potassium carbonate (310 mg, 2.2 mmol) was added to the mixture with2,2,2-trifluoroethylamine (1.2 mL, 15 mmol). Mixture was heated at 60°C. and held with stirring for 15 hours. Mixture was cooled to roomtemperature. Mixture was filtered over celite. Filtrate was concentratedby roto-vap. Residue was dissolved in a mixture of toluene (10 mL) andacetic acid (600 μL). Mixture was heated to reflux and held withstirring for 22 hours. Mixture was concentrated by roto-vap. Residue wasdissolved in ethyl acetate. Material was washed successively with waterand aqueous sodium bicarbonate. Organic phase was dried (magnesiumsulfate), filtered and concentrated to dryness. Title compound wasobtained as amber residue in 74% yield. MS m/e (M−H)⁻=431.9, 433.9.

[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid.[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (250 mg, 0.58 mmol) was reacted in a manner analogousto the preparation of [4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,1 0-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-acetic acid.Title compound was obtained as light yellow solid in quantitative yield.MS m/e (M−H)⁻=417.9, 419.9.

[4-Methyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester.[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (110 mg, 0.26 mmol) was dissolved inN,N-dimethylformamide (1.0 mL). Nitrogen gas was bubbled through themixture for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (6.0 mg,0.01 mmol) was added to the mixture followed by tetramethyltin (100 μL,0.72 mmol). Reaction vessel was flushed with nitrogen gas and thensealed. Reaction was subjected to microwave heating at 175° C. for 35minutes. Mixture was diluted with ethyl acetate. Material was washedsuccessively with water and brine. Silica gel chromatography (ethylacetate-hexanes) afforded the title compound as white solid in 83%yield. MS m/e (M+H)⁺=358.2.

[4-Methyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid.[4-Methyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (70 mg, 196 μmol) was dissolved in tetrahydrofuran(2.0 mL). Methanol (2.0 mL) was added to the mixture followed by water(2.0 mL) and then lithium hydroxide hydrate (20 mg, 477 μmol). Reactionwas warmed to 50° C. and held with stirring for 1.5 hours. Mixture wascooled to room temperature. Organic solvents were removed from themixture by roto-vap. Remaining aqueous was diluted with water and thenneutralized with 1N hydrochloric acid (500 μL). Mixture was extractedtwice with ethyl acetate. Organics were dried MgSO4, filtered and thenconcentrated to dryness. Title compound was obtained as white solid in95% yield. MS m/e (M−H)⁻=342.2.

2-(S)-(4-Acetoxymethyl-7-methyl-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester.2-(S)-(4-Acetoxymethyl-7-bromo-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester (350 mg, 0.77 mmol) and tetramethyltin (150 μL, 1.1 mmol)were reacted in a manner analogous to the preparation of[4-Methyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester. Title compound was obtained as pale yellow solid in68% yield. MS m/e (M−H)⁻=389.1.

(S)-dimethyl2-((7-methyl-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate.2-(S)-(2-Acetoxymethyl-4-amino-5-methyl-3-methyl-benzyl)-succinic aciddiethyl ester (230 mg, 0.59 mmol) was converted to the title compound ina manner analogous to the preparation of2-(S)-(4-Hydroxymethyl-1H-indazol-5-ylmethyl)-succinic acid dimethylester. Material was obtained as off-white solid in 98% yield. MS m/e(M−H)⁻=319.2.

(S)-dimethyl2-((7-methyl-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate.(S)-dimethyl2-((7-methyl-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (180 mg,0.56 mmol) was dissolved in dichloromethane (4.0 mL). 2M Thionylchloride in dichloromethane (4.0 mL, 8.0 mmol) was added to the mixture.Reaction stirred at room temperature for 2.5 hours. Mixture wasconcentrated. Residue was treated with toluene and then concentrated byroto-vap. Residue was dissolved in dichloromethane and then concentratedto dryness. Title compound was obtained as amber solid in 99% yield. MSm/e (M+H)⁺=339.1.

[4-Methyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester.2-(S)-(4-chloromethyl-7-methyl-1H-indazol-5-ylmethyl)-succinic aciddiethyl ester (190 mg, 0.56 mmol) and 2,2,2-trifluoroethylamine (45 μL,0.56 mmol) were reacted in a manner analogous to the preparation of[4-bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester. Title compound was obtained as amber residue in 76%yield. MS m/e (M+H)⁺=370.1.

[4-Methyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid.[4-Methyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (250 mg, 0.58 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as white solid in 97% yield. MS m/e(M−H)⁻=354.2.

[(S)-9-(2,2-Dimethyl-propyl)-4-isopropenyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester.[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid methyl ester (100 mg, 0.24 mmol) was dissolved in 2-propanol (1.0mL). Nitrogen gas was bubbled through the mixture for 5 minutes.Triethylamine (60 μL, 0.43 mmol) was added to the mixture followed by[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)chloride (19 mg, 0.02mmol) and potassium 2-propenyltrifluoroborate (41 mg, 0.28 mmol).Reaction vessel was flushed with nitrogen gas and then sealed. Reactionwas subjected to microwave heating at 150° C. for 30 minutes. Silica gelchromatography (ethyl acetate-hexanes) afforded the title compound asamber solid in 73% yield. MS m/e (M+H)⁺=384.4.

[(S)-9-(2,2-Dimethyl-propyl)-4-isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester.[(S)-9-(2,2-Dimethyl-propyl)-4-isopropenyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester (100 mg, 0.26 mmol) was dissolved in a mixture ofethyl acetate (5.0 mL) and methanol (5.0 mL). A catalytic amount of 10%palladium on carbon was added to the mixture. Reaction vessel was placedon a Parr apparatus and charged with 50 psi of hydrogen gas. Reactionshook at room temperature for 1 hour. Mixture was filtered and thefiltrate was concentrated to dryness. Title compound was obtained asbrown residue in 90% yield. MS m/e (M+H)⁺=386.3.

[(S)-9-(2,2-Dimethyl-propyl)-4-isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]aceticacid.[(S)-9-(2,2-Dimethyl-propyl)-4-isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester (90 mg, 0.23 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as white solid in 92% yield. MS m/e(M−H)⁻=370.3.

[4-Isopropenyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester.[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (400 mg, 0.92 mmol) and potassium2-propenyltrifluoroborate (165 mg, 1.1 mmol) were reacted in a manneranalogous to the preparation of[(S)-9-(2,2-Dimethyl-propyl)-4-isopropenyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester. Title compound was obtained as amber oil in 71%yield. MS m/e (M−H)⁻=394.1.

[4-Isopropyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2, 2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]acetic acidmethyl ester.[4-Isopropenyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (150 mg, 0.38 mmol) was reacted in a manner analogousto the preparation of[(S)-9-(2,2-Dimethyl-propyl)-4-isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester. Title compound was obtained as white solid in 73%yield. MS m/e (M+H)⁺=398.2.

[4-Isopropenyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid.[4-Isopropenyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (100 mg, 0.25 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as off-white solid in 98% yield. MSm/e (M−H)⁻=380.2.

[4-Isopropyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid.[4-Isopropyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (105 mg, 0.26 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as white solid in 99% yield. MS m/e(M−H)⁻=382.2.

[4-Ethyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2, 2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]acetic acidmethyl ester.[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (150 mg, 0.35 mmol) and tetraethyltin (200 μL, 1.0mmol) were reacted in a manner analogous to the preparation of[(S)-9-(2,2-Dimethyl-propyl)-4-methyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester. Title compound was obtained as clear colorless oil in28% yield. MS m/e (M+H)⁺=384.2.

[4-Ethyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2, 2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]acetic acid.[4-Ethyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid methyl ester (105 mg, 0.26 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as white solid in 73% yield. MS m/e(M−H)⁻=368.3.

((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-aceticacid methyl ester. (S)-dimethyl2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (630 mg,1.6 mmol) was dissolved in acetonitrile (5 mL). Potassium carbonate (560mg, 4.1 mmol) was added to the mixture followed by(aminomethyl)cyclopropane (700 μL, 8.1 mmol). Mixture was heated toreflux and held with stirring for 1.5 hours. Mixture was cooled to roomtemperature. Mixture was filtered. Filtrate was concentrated byroto-vap. Residue was dissolved in a mixture of toluene (10 mL) andacetic acid (1 mL). Mixture was heated to reflux and held with stirringfor 18 hours. Mixture was concentrated by roto-vap. Silica gelchromatography (ethyl acetate-hexanes) afforded the title compound astan solid in 64% yield. MS m/e (M+H)⁺=406.0, 408.0.

((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-aceticacid.((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-aceticacid methyl ester (290 mg, 0.71 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as yellow solid in 96% yield. MS m/e(M−H)⁻=390.0, 392.0.

[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester. (S)-dimethyl2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (400 mg,0.99 mmol) and 2-methoxyethylamine were reacted in a manner analogous tothe preparation of((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-aceticacid methyl ester. Title compound was obtained as tan solid in 66%yield. MS m/e (M−H)⁻=408.1, 410.0.

[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-acetic acid.[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid methyl ester (265 mg, 0.65 mmol) was reacted in a manner analogousto the preparation of[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid. Title compound was obtained as tan solid in 89% yield. MS m/e(M−H)⁻=394.1, 396.0.

(Z)-1-(2-(acetoxymethyl)-4-(tert-butoxycarbonylamino)-3-methylphenyl)-3-methoxy-3-oxoprop-1-en-2-ylbenzoate. 3-(tert-butoxycarbonylamino)-6-iodo-2-methylbenzyl acetate(18.0 g, 44.4 mmol) in tetrahydrofuran (180.00 ml, 2197 mmol) was addedtriethylamine (24.76 ml, 178 mmol) followed by tetrabutylammoniumchloride, hydrate (13.15 g, 44.4 mmol) and 3-methoxy-3-oxoprop-1-en-2-ylbenzoate (11.91 g, 57.7 mmol). After introducing nitrogen atmosphere,palladium(II)acetate (0.898 g, 4.0 mmol) was added. The reaction mixturewas refluxed for 3 h. The crude product was cooled and most of thesolvent was removed. The crude product was diluted with ether (300 mL)and solids were removed by filtration. The solvent was evaporated andthe crude product was purified by flash chromatography using 30% EtOAcin hexane to 50% EtOAc in hexane. The product was crystallized from amixture of EtOAc-hexane to give a white powder of(Z)-1-(2-(acetoxymethyl)-4-(tert-butoxycarbonylamino)-3-methylphenyl)-3-methoxy-3-oxoprop-1-en-2-ylbenzoate (20.5 g, 42.4 mmol, 95% yield). ¹H NMR (500 MHz, CDCl₃): in δ8.08-8.06 (m, 2H), 7.75-7.74 (m, 2H), 7.60-7.58 (m, 1H), 7.49-7.44 (m,3H), 5.25 (s, 2H), 3.85 (m, 3H), 2.24 (s, 3H), 2.07 (s, 3H), 1.52 (s,9H); MS (ESI) 506 (M+H); R_(f)=2.61.

(R)-3-(2-(acetoxymethyl)-4-(tert-butoxycarbonylamino)-3-methylphenyl)-1-methoxy-1-oxopropan-2-ylbenzoate.(Z)-1-(2-(acetoxymethyl)-4-(tert-butoxycarbonylamino)-3-methylphenyl)-3-methoxy-3-oxoprop-1-en-2-ylbenzoate (20.00 g, 41.4 mmol) in dichloromethane (120.00 ml) was added(−)-1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I)tetrafluoroborate(280.00 mg, 0.424 mmol) under nitrogen atmosphere. The reaction mixturewas hydrogenated at 60 psi pressure of hydrogen for 12h. The solvent wasremoved and crude product was carried to the next step as such. MS (ESI)508 (M+H); R_(f)=2.53.

(R)-3-(2-(acetoxymethyl)-4-amino-3-methylphenyl)-1-methoxy-1-oxopropan-2-ylbenzoate.(R)-3-(2-(acetoxymethyl)-4-(tert-butoxycarbonylamino)-3-methylphenyl)-1-methoxy-1-oxopropan-2-ylbenzoate (19.5 g, 40.2 mmol) in dichloromethane (100.00 ml, 1554 mmol)was added trifluoroacetic acid (30.00 ml, 389 mmol). The reactionmixture was stirred at RT. After 4 h, LC-MS suggested complete removalof protecting group. The solvent was removed and the crude product wasdissolved in dichloromethane (300 mL) and washed with aqueous NaHCO₃.The solvent was removed to give(R)-3-(2-(acetoxymethyl)-4-amino-3-methylphenyl)-1-methoxy-1-oxopropan-2-ylbenzoate (15.0 g, 38.9 mmol, 97% yield). MS (ESI) 408 (M+H); R_(f)=1.69.

(R)-3-(2-(acetoxymethyl)-4-amino-5-chloro-3-methylphenyl)-1-methoxy-1-oxopropan-2-ylbenzoate.(R)-3-(2-(acetoxymethyl)-4-amino-3-methylphenyl)-1-methoxy-1-oxopropan-2-ylbenzoate (15.00 g, 38.9 mmol) in acetonitrile (200. ml, 3829 mmol) wasadded N-chlorosuccinimide (5.72 g, 42.8 mmol). The reaction mixture wasthen heated to reflux for 2 min. The solvent was removed and the crudeproduct was washed with aqueous NaHCO₃. The crude product was purifiedby flash chromatography using 30% EtOAc in hexane to give(R)-3-(2-(acetoxymethyl)-4-amino-5-chloro-3-methylphenyl)-1-methoxy-1-oxopropan-2-ylbenzoate in 57% yield. MS (ESI) 442 (M+H); R_(f)=2.42.

(R)-3-(4-(acetoxymethyl)-7-chloro-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-ylbenzoate.(R)-3-(2-(acetoxymethyl)-4-amino-5-chloro-3-methylphenyl)-1-methoxy-1-oxopropan-2-ylbenzoate (16.33 g, 38.9 mmol) in toluene (100.0 ml, 939 mmol) was addedacetic acid (5.0 ml, 87 mmol) followed by isoamyl nitrite (5.76 ml, 42.8mmol) at 0° C. After 15 min, potassium acetate (7.64 g, 78 mmol) wasadded and the reaction mixture was stirred for 12 h. The solvent wasremoved and the crude product was dissolved in dichloromethane (250 mL)and washed with aqueous NaHCO₃. The solvent was dried (Na₂SO₄),evaporated and the crude product was purified by flash chromatographyusing 40% EtOAc in hexane to give(R)-3-(4-(acetoxymethyl)-7-chloro-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-ylbenzoate in 88% yield. MS (ESI) 453 (M+Na); R_(f)=2.46.

(R)-3-(7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-ylbenzoate.(R)-3-(4-(acetoxymethyl)-7-chloro-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-ylbenzoate (8.5g, 19.73 mmol) in a mixture of chloroform (80.0 ml, 992mmol) and methanol (60.0 ml, 1483 mmol) was added magnesium methoxide(4.18 ml, 39.5 mmol). After 3 h, quenched with 1.0 M HCl and extractedwith dichloromethane (300 mL). The crude product was purified by flashchromatography using 70% EtOAc in hexane to give(R)-3-(7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-ylbenzoate in 67% yield. ¹H NMR (500 MHz, CDCl₃): in δ 8.09 (s, 1H), 7.93(d, J=7.5 Hz, 1H), 7.47 (m, 1H), 7.32 (t, J=8 Hz, 2H), 7.22 (s, 1H),5.49 (m, 1H), 4.99 (m, 2H), 3.45-3.41 (m, 1H), 3.68 (s, 3H), 3.36-3.31(m, 1H); MS (ESI) 389 (M+H); R_(f)=2.07.

(R)-3-(7-chloro-4-(chloromethyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-ylbenzoate.(R)-3-(7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-ylbenzoate (6.5 g, 16.72 mmol) in dichloromethane (100.0 ml, 1554 mmol)was added Diisopropylethyl amine (2.59 g, 20.06 mmol) followed bymethanesulfonyl chloride (1.433 ml, 18.39 mmol). After 2 h, the reactionmixture was quenched with aqueous NaHCO₃, dried (Na₂SO₄) and the solventwas removed. MS (ESI) 407 (M+H); R_(f)=1.69.

(R)-3-(7-chloro-4-((2,2,2-trifluoroethylamino)methyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-ylbenzoate.(R)-3-(7-chloro-4-(chloromethyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-ylbenzoate (6.80 g, 16.7 mmol) in acetonitrile (70.0 ml, 1340 mmol) wasadded 2,2,2-trifluoroethylamine (8.27 g, 84 mmol). After 20 min,potassium carbonate (2.308 g, 16.70 mmol) was added and the reactionmixture was refluxed for 2 h. The solvent was evaporated and the crudeproduct was dissolved in a mixture of dichloromethane and chloroform. Athick emulsion formed and addition of methanol provided a clear organicphase. The organic layer was dried (Na₂SO₄), the solvent was removed andthe crude product was used as such for the next step. MS (ESI) 470(M+H); R_(f)=1.56.

(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylbenzoate.(R)-3-(7-chloro-4-((2,2,2-trifluoroethylamino)methyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-ylbenzoate (7.75 g, 16.5 mmol) in toluene (70.00 ml, 657 mmol) was addedacetic acid (1.2 ml, 20.96 mmol) and refluxed for 12 h. The solvent wasevaporated and the crude product was dissolved in EtOAc, washed withaqueous NaHCO₃. The solvent was removed and the crude product waspurified by flash chromatography using 50% EtOAc in hexane to give(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylbenzoate in 74% yield. MS (ESI) 438 (M+H); R_(f)=2.60.

(R)-4-chloro-7-hydroxy-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylbenzoate (7.00 g, 16.0 mmol) in THF (60.00 ml, 732 mmol) was addedlithium hydroxide (0.766 g, 32.0 mmol) followed by water (6.0 ml, 333mmol). After 3 h, the solvent was removed and the crude product wasdiluted with dichloromethane and neutralized with 1.0 M HCl. The organicphase was dried and the crude product was purified by flashchromatography using 70% EtOAc in hexane to give(R)-4-chloro-7-hydroxy-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-onein 53% yield. ¹H NMR (500 MHz, CDCl₃): in δ 8.12 (s, 1H), 7.16 (s, 1H),5.18-5.14 (m, 2H), 4.55 (d, J=17 Hz, 1H), 4.30-4.28 (m, 1H), 4.27-4.24(m, 1H), 3.86 (m, 1H), 3.46 (dd, J=5 Hz, J=1.5 Hz, 1H), 3.09 (dd, J=5Hz, J=1.5 Hz, 1H), 1.52 (s, 9H); MS (ESI) 334 (M+H); R_(f)=1.49.

(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl4-nitrophenyl carbonate.(R)-4-chloro-7-hydroxy-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(1.2 g, 3.60 mmol) in dichloromethane (100.0 ml, 1554 mmol) was addeddiisopropylethyl amine (0.651 g, 5.03 mmol) followed by 4-nitrophenylcarbonochloridate (0.942 g, 4.67 mmol). After 48 h, the reaction mixturewas washed with 1.0 M HCl and the crude product was purified by flashchromatography using 75% EtOAc in hexane to give(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl4-nitrophenyl carbonate (1.0 g, 2.005 mmol, 56% yield). MS (ESI) 499(M+H) ; R_(f)=1.64.

(R)-benzyl4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate.(R)-Methyl2-(benzyloxycarbonyl)-3-(7-chloro-4-(chloromethyl)-1H-indazol-5-yl)propanoate(630 mg, 1444 μmol) was dissolved in acetonitrile (15 ml). Potassiumcarbonate (240 mg, 1737 μmol) was added to the mixture followed by2,2,2-Trifluoroethylamine (400 μl, 5028 μmol). Mixture was warmed toreflux and held with stirring for 1 hour. Another 1 mL of2,2,2-trifluoroethylamine was added to the mixture followed by another320 mg of potassium carbonate. Mixture was heated at reflux for 45minutes. Mixture was cooled to room temperature and then filtered overcelite. Filtrate was concentrated by roto-vap. Residue was dissolved intoluene (15 ml). Acetic acid (0.50 ml, 8734 μmol) was added to themixture. Reaction was warmed to reflux and held for 16 hours. Mixturewas concentrated by roto-vap. Silica gel chromatography eluting ethylacetate-hexanes afforded the desired product as tan solid in 67% yield.MS (M+H)⁺=466.8.

(R)-7-amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(R)-Benzyl4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-ylcarbamate(450 mg, 964 μmol) was dissolved in dichloromethane (20 ml). Anisole(250 μl, 2300 μmol) was added to the mixture followed by methanesulfonicacid (5.0 ml, 77051 μmol). Reaction stirred at room temperature for 1.5hours. 100 mL of diethyl ether was added to the mixture. Reactionstirred at room temperature for 45 minutes. Liquids were decanted off.Remaining solid was washed with diethyl ether and the liquids decanted.Solids were dissolved in water. Mixture was made basic with aqueoussodium bicarbonate. Mixture was extracted twice with ethyl acetate andthe aqueous phase was discarded. Material was washed successively withaqueous sodium bicarbonate, water and brine and the aqueous phases werediscarded. Organics were dried MgSO₄, filtered and then concentrated todryness. Title compound was obtained as light yellow solid in 78% yield.MS (M+H)⁺=321.2.

(S)-diethyl2-((4-(acetoxymethyl)-3,7-dibromo-1H-indazol-5-yl)methyl)succinate.(S)-Diethyl2-((4-(acetoxymethyl)-7-bromo-1H-indazol-5-yl)methyl)succinate (555 mg,1.219 mmol) was dissolved in dichloromethane (20 mL). N-Bromosuccinimide(250 mg, 1.405 mmol) was added to the mixture followed by a small amountof silica gel. Reaction stirred at room temperature for 1 hour. Mixturewas concentrated some by roto-vap. Silica gel chromatography elutingethyl acetate-hexanes afforded the title compound as clear colorless oilin 84% yield. MS (M−H)⁻=533.1, 531.2, 535.1.

(S)-dimethyl2-((3,7-dibromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate.(S)-Diethyl2-((4-(acetoxymethyl)-3,7-dibromo-1H-indazol-5-yl)methyl)succinate (540mg, 1.011 mmol) was dissolved in methanol (12 mL). 6-10% Magnesiummethoxide solution in methanol (2.7 mL, 2.041 mmol) was added to themixture. Reaction stirred at room temperature for 18 hours. Reaction wasquenched with 5 mL 1N hydrochloric acid. Mixture stirred at roomtemperature for 30 minutes. Methanol was removed from the mixture byroto-vap. Residue was dissolved in water and then made basic withaqueous sodium bicarbonate. Material was extracted twice with ethylacetate and the aqueous phase was discarded. Organics were dried MgSO₄,filtered and then concentrated to dryness. Title compound was obtainedas white foam in 99% yield. 1H NMR, MS (M−H)⁻=463.1, 461.1, 465.1.

(S)-methyl 2-(1,4-dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate. (S)-Dimethyl2-((3,7-dibromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (460mg, 0.991 mmol) was dissolved in thionyl chloride (2.0 M. indichloromethane) (496 μl, 0.992 mmol). Reaction stirred at roomtemperature for 4 hours. Mixture was concentrated by roto-vap. Residuewas dissolved in ethyl acetate. Material was washed twice with aqueoussodium bicarbonate and the aqueous phase was discarded. Organics weredried MgSO₄, filtered and then concentrated to dryness. Residue (415 mg,0.860 mmol) was dissolved in acetonitrile (15 mL). Potassium carbonate(165 mg, 1.194 mmol) was added to the mixture followed by2,2,2-trifluoroethylamine (350 μl, 4.40 mmol). Mixture was warmed toreflux and held with stirring for 30 minutes. Mixture was cooled to roomtemperature. Mixture was filtered over celite. Filtrate was concentratedby roto-vap. Residue was dissolved in toluene (17 mL). Acetic acid (200μl, 3.49 mmol) was added to the mixture. Reaction was warmed to refluxand held with stirring for 16 hours. Mixture was cooled to roomtemperature and then diluted with ethyl acetate. Mixture was washed withaqueous sodium bicarbonate and the aqueous phase was discarded. Organicswere dried MgSO₄, filtered and then concentrated to dryness. Silica gelchromatography eluting ethyl acetate-hexanes afforded the title compoundas white solid in 45% yield. MS (M−H)⁻=512.1, 510.1, 514.1.

(S)-2-(1,4-dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid. (S)-Methyl2-(1,4-dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate(220 mg, 0.429 mmol) was dissolved in a mixture of methanol (5.0 mL) andtetrahydrofuran (5.0 mL). Water (5.0 mL) was added to the mixturefollowed by lithium hydroxide hydrate (66.0 mg, 1.573 mmol). Reactionwas warmed to 60° C. and held with stirring for 1.25 hours. Mixture wascooled to room temperature and then neutralized with 1.6 mL 1Nhydrochloric acid. Mixture was concentrated by roto-vap. Residue waspartitioned between ethyl acetate and water. Layers were separated andthe aqueous phase was discarded. Material was washed with brine and theaqueous phase was discarded. Organics were dried MgSO₄, filtered andthen concentrated to dryness. Title compound was obtained as white solidin 96% yield. MS (M−H)⁻=498.1, 496.1, 500.1.

(S)-methyl2-(4-bromo-8-oxo-6,7,8,10-tetrahydro-3H-oxepino[3,4-e]indazol-7-yl)acetate.(S)-Dimethyl2-((3,7-dibromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (440mg, 1.065 mmol) was dissolved in toluene (30 mL). p-Toluenesulfonic acidmonohydrate (28 mg, 0.147 mmol) was added to the mixture. Reaction waswarmed to reflux and held for 18 hours with stirring. Mixture was cooledto room temperature and then diluted with ethyl acetate. Material waswashed with aqueous sodium bicarbonate and the aqueous phase wasdiscarded. Organics were dried MgSO₄, filtered and then concentrated todryness. Silica gel chromatography eluting ethyl acetate-hexanesafforded the title compound as amber oil in 42% yield. MS (M+H)⁺=367.2,369.2.

(S)-2-((7-bromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinic acid.(S)-Methyl2-(4-bromo-8-oxo-6,7,8,10-tetrahydro-3H-oxepino[3,4-e]indazol-7-yl)acetate(135 mg, 0.368 mmol) was dissolved in a mixture of tetrahydrofuran (4.0mL) and methanol (4.0 mL). Water (4.0 mL) was added to the mixturefollowed by lithium hydroxide hydrate (31.5 mg, 0.751 mmol). Reactionstirred at room temperature for 5 hours. Another 30 mg of lithiumhydroxide hydrate was added to the mixture. Reaction stirred at roomtemperature for 18 hours. Reaction was quenched with 1.6 mL 1Nhydrochloric acid. Organic solvents were removed from the mixture byroto-vap. Material was extracted from the remaining aqueous twice withethyl acetate and the aqueous phase was discarded. Organics were driedMgSO₄, filtered and then concentrated to dryness. Title compound wasobtained as white solid in 73% yield. MS (M−H)⁻=355.2, 357.1.

(S)-2-(4-bromo-8-oxo-6,7,8,10-tetrahydro-3H-oxepino[3,4-e]indazol-7-yl)aceticacid. (S)-2-((7-Bromo-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinicacid (95 mg, 0.266 mmol) was suspended in toluene (15 mL).p-Toluenesulfonic acid monohydrate (3.5 mg, 0.018 mmol) was added to themixture. Reaction was warmed to reflux and held with stirring for 18hours. Mixture was concentrated to dryness. Title compound was obtainedas tan solid in 99% yield. LCMS (M−H)⁻=339.0, 337.0.

(S)-diethyl2-((4-(acetoxymethyl)-7-bromo-3-chloro-1H-indazol-5-yl)methyl)succinate.(S)-Diethyl2-((4-(acetoxymethyl)-7-bromo-1H-indazol-5-yl)methyl)succinate (400 mg,0.879 mmol) was dissolved in N,N-dimethylformamide (5.0 ml).N-Chlorosuccinimide (130 mg, 0.974 mmol) was added to the solution.Mixture was warmed to 150° C. and held with stirring for 1.5 hours.Mixture was cooled to room temperature and then diluted with ethylacetate. Material was washed twice with water and the aqueous phase wasdiscarded. Material was washed with brine and the aqueous phase wasdiscarded. Organics were dried MgSO4, filtered and then concentrated todryness. Silica gel chromatography eluting ethyl acetate-hexanesafforded the title compound as clear colorless oil in 88% yield. MS(M+H)⁺=491.0.

(S)-dimethyl2-((7-bromo-3-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate.(S)-Diethyl2-((4-(acetoxymethyl)-7-bromo-3-chloro-1H-indazol-5-yl)methyl)succinate(550 mg, 1.123 mmol) was dissolved in methanol (15 mL, 370 mmol). 6-10%Magnesium methoxide in methanol (3.4 mL, 2.57 mmol) was added to themixture. Reaction stirred at room temperature for 18 hours. Reaction wasquenched with 6 mL of 1N hydrochloric acid. Mixture stirred at roomtemperature for 10 minutes. Mixture was concentrated by roto-vap.Residue was suspended in water. Mixture was made basic with aqueoussodium bicarbonate. Material was extracted twice and the aqueous phasewas discarded. Organics were dried MgSO₄, filtered and then concentratedto dryness. Title compound was obtained as white solid in 96% yield. MS(M−H)⁻=419.0.

(S)-methyl2-(4-bromo-1-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate.(S)-Dimethyl2-((7-bromo-3-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate(450 mg, 1.072 mmol) was dissolved in thionyl chloride (2.0 M indichloromethane) (5.0 mL, 10.00 mmol). Reaction stirred at roomtemperature for 2.5 hours. Mixture was concentrated by roto-vap. Residuewas dissolved in ethyl acetate. Material was washed twice with aqueoussodium bicarbonate and the aqueous phase was discarded. Organics weredried MgSO₄, filtered and then concentrated to dryness. Residue (430 mg,0.982 mmol) was dissolved in acetonitrile (15 mL).2,2,2-Trifluoroethylamine (400 μl, 5.03 mmol) was added to the mixturefollowed by potassium carbonate (195 mg, 1.411 mmol). Mixture was warmedto reflux and held with stirring for 30 minutes. Mixture was cooled toroom temperature. Mixture was filtered over celite. Filtrate wasconcentrated by roto-vap. Residue was dissolved in toluene (15 mL).Acetic acid (500 μl, 8.73 mmol) was added to the mixture. Reaction waswarmed to reflux and held with stirring for 14 hours. Mixture was cooledto room temperature. Mixture was diluted with ethyl acetate. Materialwas washed twice with aqueous sodium bicarbonate and the aqueous phasewas discarded. Organics were dried MgSO₄, filtered and then concentratedto dryness. Silica gel chromatography eluting ethyl acetate-hexanesafforded the title compound as white solid in 46% yield. MS(M−H)⁻=467.9.

(S)-2-(4-bromo-1-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid. (S)-Methyl2-(4-bromo-1-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate(210 mg, 0.448 mmol) was dissolved in a mixture of tetrahydrofuran (3.0ml) and methanol (3.0 ml). Water (3.00 ml) was added to the mixturefollowed by lithium hydroxide hydrate (30 mg, 0.715 mmol). Reaction waswarmed to 50° C. and held with stirring for 5 hours. Mixture was cooledto room temperature and allowed to stand for 64 hours. More lithiumhydroxide hydrate (24.9 mg, 0.593 mmol) was added to the mixture.Reaction was warned to 50° C. and held for 3 hours. Mixture was cooledto room temperature. Organic solvents were removed from the mixture byroto-vap. Residue was diluted with water. Mixture was neutralized with1.4 mL 1N hydrochloric acid. Material was extracted twice with ethylacetate and the aqueous phase was discarded. Organics were dried MgSO₄,filtered and then concentrated to dryness. Title compound was obtainedas off-white solid in quantitative yield. LCMS (M−H)⁻=453.9.

(S)-diethyl2-((4-(acetoxymethyl)-3,7-dichloro-1H-indazol-5-yl)methyl)succinate.(S)-Diethyl2-((4-(acetoxymethyl)-7-chloro-1H-indazol-5-yl)methyl)succinate (1.12 g,2.73 mmol) was dissolved in N,N-dimethylformamide (30 ml). Mixture waswarmed to 70° C. N-Chlorosuccinimide (400 mg, 3.00 mmol) was added tothe solution. Mixture was warmed to 150° C. and held with stirring for30 minutes. Mixture was cooled to room temperature and then diluted withethyl acetate. Material was washed twice with 1N sodium thiosulfate andthe aqueous phase was discarded. Material was washed successively withwater and brine and the aqueous phases were discarded. Organics weredried MgSO₄, filtered and then concentrated to dryness. Title compoundwas obtained as dark amber oil in quantitative yield. MS (M−H)⁻=443.0.

(S)-dimethyl2-((3,7-dichloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate.(S)-Diethyl2-((4-(acetoxymethyl)-3,7-dichloro-1H-indazol-5-yl)methyl)succinate(1.30 g, 2.92 mmol) was dissolved in methanol (45 mL). 6-10% Magnesiummethoxide in methanol (8.4 mL, 6.35 mmol) was added to the mixture.Reaction stirred at room temperature for 16 hours. Reaction was quenchedwith 14 mL 1N hydrochloric acid. Methanol was removed from the mixtureby roto-vap. Residue was treated with aqueous sodium bicarbonate.Material was extracted twice with ethyl acetate and the aqueous phasewas discarded. The combined organic phases were washed with water andthe aqueous phase was discarded. Organics were dried MgSO₄, filtered andthen concentrated to dryness. Title compound was obtained as dark amberoil in 91% yield. MS (M−H)⁻=373.0, 375.0.

(S)-methyl2-(1,4-dichloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate.(S)-Dimethyl2-((3,7-dichloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (990mg, 2.64 mmol) was dissolved in thionyl chloride (2.0 M indichloromethane) (20 mL, 40.0 mmol). Mixture stirred at room temperaturefor 3 hours. Mixture was concentrated by roto-vap. Residue was dissolvedin ethyl acetate. Mixture was washed twice with aqueous sodiumbicarbonate. Organics were dried MgSO₄, filtered and then concentratedto dryness. A portion of the residue (535 mg, 1.359 mmol) was dissolvedin acetonitrile (15 mL). 2,2,2-Trifluoroethylamine (600 μl, 7.57 mmol)was added to the mixture followed by potassium carbonate (225 mg, 1.628mmol). Mixture was warmed to reflux and held with stirring for 1 hour.Mixture was cooled to room temperature and then filtered over celite.Filtrate was concentrated by roto-vap. Residue was dissolved in toluene(15 mL). Acetic acid (500 μl, 8.73 mmol) was added to the mixture.Reaction was warmed to reflux and held with stirring for 14 hours.Mixture was cooled to room temperature and then diluted with ethylacetate. Material was washed twice with aqueous sodium bicarbonate andthe aqueous phase was discarded. Organics were dried MgSO₄, filtered andthen concentrated to dryness. Silica gel chromatography eluting ethylacetate-hexanes afforded the title compound as off-white solid in 42%yield. MS (M+H)⁺=423.9, 425.9.

(S)-methyl2-(1,4-dichloro-8-oxo-9-(2-(piperidin-1-yl)ethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate.(S)-Dimethyl2-((3,7-dichloro-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (990mg, 2.64 mmol) was dissolved in thionyl chloride (2.0 M indichloromethane) (20 mL, 40.0 mmol). Mixture stirred at room temperaturefor 3 hours. Mixture was concentrated by roto-vap. Residue was dissolvedin ethyl acetate. Mixture was washed twice with aqueous sodiumbicarbonate. Organics were dried MgSO₄, filtered and then concentratedto dryness. A portion of the residue (460 mg, 1.169 mmol) was dissolvedin acetonitrile (15 mL). 1-(2-Aminoethyl)-piperidine (600 μl, 4.21 mmol)was added to the mixture followed by potassium carbonate (200 mg, 1.447mmol). Mixture was warmed to reflux and held with stirring for 1 hour.Mixture was cooled to room temperature and then filtered over celite.Filtrate was concentrated by roto-vap. Residue was dissolved in toluene(15 mL). Acetic acid (1.0 mL, 17.47 mmol) was added to the mixture.Reaction was warmed to reflux and held with stirring for 16 hours.Mixture was cooled to room temperature and then concentrated byroto-vap. Residue was suspended in ethyl acetate. Mixture was washedtwice with aqueous sodium bicarbonate and the aqueous phase wasdiscarded. Organics were dried MgSO₄, filtered and then concentrated todryness. Silica gel chromatography eluting 2M ammonia inmethanol-dichloromethane afforded the title compound as amber oil in 51%yield. (M+H)⁺=453.0, 455.0.

(S)-2-(1,4-dichloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid. (S)-Methyl2-(1,4-dichloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate(230 mg, 0.542 mmol) was dissolved in a mixture of tetrahydrofuran (5.0mL) and methanol (5.0 mL). Water (5.0 mL) was added to the mixturefollowed by lithium hydroxide hydrate (66 mg, 1.573 mmol). Reaction waswarmed to 50° C. and held with stirring for 4.5 hours. Mixture wascooled to room temperature. Organic solvents were removed from themixture by roto-vap. Residue was neutralized with 1.6 mL 1N hydrochloricacid. Material was extracted twice with ethyl acetate and the aqueousphase was discarded. Organics were dried MgSO₄, filtered and thenconcentrated to dryness. Title compound was obtained as white solid in94% yield. MS (M−H)⁻=407.9, 409.9.

(S)-2-(1,4-dichloro-8-oxo-9-(2-(piperidin-1-yl)ethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid. (S)-Methyl2-(1,4-dichloro-8-oxo-9-(2-(piperidin-1-yl)ethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate(260 mg, 0.573 mmol) was dissolved in a mixture of tetrahydrofuran (5.0mL, 61.6 mmol) and methanol (5.0 mL, 123 mmol). Water (5.0 mL, 278 mmol)was added to the mixture followed by lithium hydroxide hydrate (65 mg,1.549 mmol). Mixture was warmed to 50° C. and held with stirring for 4.5hours. Mixture was cooled to room temperature. Organic solvents wereremoved from the mixture by roto-vap. Residue was neutralized with 1.6mL 1N hydrochloric acid and treated with ethyl acetate. Mixture sat atroom temperature for 20 minutes allowing solids to form. Solids werefiltered off and washed with water. Solids were dried in vacuo. Titlecompound was obtained as white solid in 50% yield. MS (M−H)⁻=437.1,439.2.

EXAMPLE 1

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(9-benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-amide.Potassium carbonate (25 mg, 0.18 mmol) was added to a solution of4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(3-acetyl-9-benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-amide(19 mg, 0.03 mmol). Reaction was stirred at room temperature for 1.25hours. Reaction was quenched with 1N hydrochloric acid (5 mL). Methanolwas removed from the mixture in vacuo. Remaining aqueous was made basicwith sodium bicarbonate. Mixture was extracted with dichloromethane(3×10 mL). Combined extracts were dried (magnesium sulfate), filteredand concentrated in vacuo. Title compound was obtained as an off-whitesolid in 90% yield. ¹H NMR (300 MHz, CDCl₃): δ=7.64 (s, 1H), 7.18 (m,6H), 7.06 (m, 1H), 6.96 (t, J=7.1, 1H), 6.84 (m, 2H), 6.67 (m, 1H), 6.24(d, J=5.9, 1H), 5.40 (m, 1H), 4.96 (d, J=14.6, 1H), 4.76 (d, J=17.2,1H), 4.58 (m, 2H), 4.15 (m, 5H), 3.83 (d, J=13.2, 1H), 3.46 (dd, J1=3.1J2=16.7, 1H), 2.98 (m ,3H), 1.78 (m, 4H). MS m/e (M+H)⁺=564.3.

EXAMPLE 2

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(9-methyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-amide.A catalytic amount of 10% palladium on carbon was added to a mixture of(3-acetyl-9-methyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester (30 mg, 0.07 mmol), and acetic acid (20 μL, 0.35 mmol)in methanol (6 mL) and ethyl acetate (3 mL). Reaction vessel was placedon a Parr hydrogenation apparatus and charged with 50 psi of hydrogengas. Reaction mixture was allowed to shake at room temperature for 1.5hours. Mixture was filtered. Filtrate was concentrated. Residue wastreated with dichloromethane (3 mL) and saturated aqueous sodiumbicarbonate (1 mL). 20% phosgene in toluene (48 μL, 0.09 mmol) was addedto the mixture. Reaction was stirred at room temperature for 5 minutes.4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidinium acetate (25 mg,0.09 mmol) was added to the mixture. Reaction mixture was allowed tostir at room temperature for 1 hour. Another 20 μL of phosgene solutionwas added to the mixture followed after 15 minutes by another 20 mg of4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidinium acetate. Reactionmixture was stirred at room temperature for 30 minutes. Reaction layerswere partitioned. Organic was washed successively with 1N hydrochloricacid (2×5 mL), and brine (5 mL). Organic was dried (magnesium sulfate),filtered and concentrated in vacuo. Residue was dissolved in methanol (3mL). Potassium carbonate (25 mg, 0.18 mmol) was added to the mixture.Reaction mixture was stirred at room temperature for 1 hour. Reactionwas quenched with a couple of drops of trifluoroacetic acid. C18preparatory HPLC (acetonitrile-water-trifluoroacetic acid) yielded thetitle compound as a white solid in 16% yield. ¹H NMR (300 MHz, CDCl₃):δ=7.94 (s, 1H), 7.17 (m, 2H), 7.06 (t, J=7.1, 2H), 6.93 (m, 2H), 6.82(d, J=9.2, 1H), 6.66 (d, J=7.3, 1H), 6.19 (d, J=5.9, 1H), 5.37 (m, 1H),5.16 (m, 1H), 5.03 (d J=17.2, 1H), 4.59 (m, 1H), 4.34 (s, 3H), 4.19 (m,2H), 3.42 (m, 1H), 2.94 (m, 4H), 1.80 (m, 4H). MS m/e (M+H)⁺=488.4.

EXAMPLE 3

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.N,N′-Disuccinimidyl carbonate (55 mg, 0.21 mmol) was added to a mixtureof7-(R)-amino-9-(2-piperidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one(60 mg, 0.18 mmol) and triethylamine (150 μl, 1.1 mmol) indichloromethane (3 mL). Reaction was stirred at room temperature for 30minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidinium acetate(65 mg, 0.22 mmol) was added to the reaction mixture. Reaction wasstirred until judged complete by HPLC (1.75 hours). Mixture was washedsuccessively with water (2×5 mL) and brine (1×5 mL). Organic wasconcentrated in vacuo. C18 preparatory HPLC(acetonitrile-water-trifluoroacetic acid) afforded the desired productas a tan solid in 34% yield. ¹H NMR (300 MHz, DMSO-D₆): δ=9.23 (s, 1H),8.34 (s, 1H), 7.43 (d, J=8.8, 1H), 7.13 (m, 2H), 6.86 (t, J=7.0, 1H),6.77 (d, J=7.7, 1H), 6.68 (d, J=7.7, 1H), 5.26 (m, 2H), 4.71 (d, J=17.2,1H), 4.36 (m, 1H), 4.13 (m, 4H), 3.48 (m, 2H), 3.26 (m, 2H), 3.08 (m,1H), 2.92 (m, 2H), 2.80 (m, 2H), 1.80 (m, 2H), 1.62 (m, 4H). MS m/e(M+H)⁺=585.4.

EXAMPLE 4

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-pyrrolidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.7-(R)-Amino-9-(2-pyrrolidin-1-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one(27 mg, 0.09 mmol) was reacted in a manner analogous to the preparationof 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.Title compound was obtained as a white solid in 20% yield. ¹H NMR (300MHz, DMSO-D₆): δ=9.23 (s, 1H), 8.34 (s, 1H), 7.43 (d, J=8.4, 1H), 7.13(m, 2H), 6.86 (t, J=7.3, 1H), 6.76 (d, J=7.7, 1H), 6.67 (d, J=7.0, 1H),5.26 (m, 2H), 4.70 (d, J=17.2, 1H), 4.37 (m, 2H), 4.12 (m, 6H), 3.62 (m,2H), 3.36 (m, 4H), 3.04 (m, 3H), 2.80 (m, 2H), 2.00 (m, 2H), 1.86 (m,2H), 1.70 (m, 2H), 1.57 (m, 2H). MS m/e (M+H)⁺=571.4.

EXAMPLE 5

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[9-(2-dimethylamino-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.7-(R)-Amino-9-(2-dimethylamino-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one(11 mg, 0.04 mmol) was reacted in a manner analogous to the preparationof 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.Desired compound was obtained as a white solid in 34% yield. ¹H NMR (300MHz, DMSO-D₆): δ=9.23 (s, 1H), 8.34 (s, 1H), 7.42 (d, J=8.4, 1H), 7.12(m, 2H), 6.87 (t, J=7.5, 1H), 6.77 (d, J=8.1, 1H), 6.64 (d, J=7.3, 1H),5.26 (m, 2H), 4.69 (d, J=17.2, 1H), 4.36 (m, 1H), 4.13 (m, 6H), 3.37 (m,2H), 3.21 (m, 2H), 3.05 (m, 2H), 2.82 (m, 8H), 1.71 (m, 2H), 1.57 (m,2H). MS m/e (M+H)⁺=545.4.

EXAMPLE 6

5-Neopentyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)ethyl)-7,8-dihydro-1H-pyrazolo[3,4-g]quinolin-6(5H)-one.O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (116 mg, 0.3 mmol) was added to a solution of2-(1-neopentyl-2-oxo-2,3,4,7-tetrahydro-1H-pyrazolo[3,4-h]quinolin-3-yl)aceticacid (95 mg, 0.3 mmol) and N,N-diisopropylethylamine (158 μL, 0.9 mmol)in dichloromethane (5.0 mL). Mixture was stirred at room temperature for45 minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine (70 mg,0.3 mmol) was then added to the mixture. After 3 h stirring at roomtemperature, the crude reaction mixture was purified by prep HPLCstarting from 30% methanol in water to 90% methanol in water over aperiod of 8 min and at a flow rate of 40 ml/min. Removal of solventfurnished the desired. MS (ESI) 529 (M+H); R_(f)=1.57.

EXAMPLE 7

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[9-(2-morpholin-4-yl-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.7-(R)-Amino-9-(2-morpholin-4-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one(18 mg, 0.05 mmol) was reacted in a manner analogous to the preparationof 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.The title compound was obtained as a light yellow solid in 43% yield. ¹HNMR (300 MHz, DMSO-D₆): δ=9.23 (s, 1H), 8.33 (s, 1H), 7.44 (d, J=8.4,1H), 7.13 (t, J=8.4, 2H), 6.86 (t, J=7.5, 1H), 6.77 (d, J=8.4, 1H), 6.66(d, J=7.0, 1H), 5.27 (m, 2H), 4.71 (d, J=17.2, 1H), 4.38 (m, 1H), 4.16(m, 4H), 3.98 (m, 2H), 3.61 (m, 4H), 3.42 (m, 4H), 3.29 (m, 2H), 3.10(m, 4H), 2.79 (m, 2H), 1.72 (m, 2H), 1.56 (m, 2H), 1.56 (m, 2H). MS m/e(M+H)⁺=587.4.

EXAMPLE 8

′H-Spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one-1-carboxylic acid[9-(2-morpholin-4-yl-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.N,N′-Disuccinimidyl carbonate (21 mg, 0.08 mmol) was added to a mixtureof7-(R)-Amino-9-(2-morpholin-4-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one(22 mg, 0.07 mmol) and triethylamine (40 μL, 0.29 mmol) indichloromethane (1 mL). Reaction was stirred at room temperature for 30minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidinium acetate(65 mg, 0.22 mmol) was added to the reaction mixture. Reaction wasstirred until judged complete by HPLC (1.5 hours). Mixture wasconcentrated in vacuo. C18 preparatory HPLC(acetonitrile-water-trifluoroacetic acid) afforded the desired productas a white solid in 34% yield. ¹H NMR (300 MHz, DMSO-D₆): δ=9.26 (s,1H), 8.34 (s, 1H), 7.43 (d, J=8.8, 1H), 7.18 (m, 3H), 6.91 (t J=7.0,1H), 6.83 (d, J=8.1, 1H), 6.66 (d, J=7.0, 1H), 5.28 (m, 2H), 4.70 (d,J=17.6, 1H), 3.62 (m, 6H), 3.62 (m, 4H), 3.41 (m, 4H), 3.27 (m, 4H),3.09 (m, 2H), 1.86 (m, 2H), 1.72 (m, 2H). MS m/e (M+H)⁺=573.4.

EXAMPLE 9

′¹H-Spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one-1-carboxylic acid[8-oxo-9-(1-(S)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.7-Amino-9-(1-(S)-phenyl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-8-one(27 mg, 0.08 mmol) was reacted in a manner analogous to the preparationof ¹H-spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one-1-carboxylic acid[9-(2-morpholin-4-yl-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.The title compound was obtained as a white solid in 14% yield. ¹H NMR(300 MHz, CD₃OD): δ=7.92 (s, 1H), 7.46 (m, 5H), 7.37 (m, 1H), 7.30 (m,1H), 7.19 (m, 2H), 7.00 (t J=7.7, 1H), 6.85 (d, J=7.7, 1H), 5.98 (q,J=6.8, 1H), 5.46 (dd, J1=4.6, J2=13.0, 1H), 4.98 (d, J=17.2, 1H), 4.90(m, 1H), 4.37 (d, J=17.6, 1H), 4.11 (m, 2H), 3.40 (m, 4H), 3.22 (m, 2H),2.12 (m, 2H), 1.92 (d, J=13.5, 2H), 1.24 (d, J=7.3, 3H). MS m/e(M+H)⁺=564.1.

EXAMPLE 10

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(1-(S)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.7-Amino-9-(1-(S)-phenyl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-8-one(27 mg. 0.08 mmol) was reacted in a manner analogous to the preparationof 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.Title compound was obtained as a white solid in 20% yield. ¹H NMR (300MHz, CD₃OD): δ=7.92 (s, 1H), 7.47 (m, 5H), 7.43 (d, J=8.8, 1H), 7.21 (d,J=8.8, 1H), 7.12 (m, 2H), 6.95 (t, J=7.0, 1H), 6.78 (d, J=7.7, 1H), 5.98(d, J=7.0, 1H), 5.44 (dd, J1=4.4, J2=13.7, 1H), 4.98 (d, J=17.2, 1H),4.49 (m, 1H), 4.41 (m, 3H), 4.31 (m, 4H), 3.36 (m, 1H), 3.24 (m, 1H),2.99 (m, 2H), 1.93 (m, 2H), 1.73 (m, 2H), 1.24 (d, J=7.0, 3H). MS m/e(M+H)⁺=578.2.

EXAMPLE 11

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(1-(R)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.7-Amino-9-(1-(R)-phenyl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-8-one(48 mg. 0.15 mmol) was reacted in a manner analogous to the preparationof 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.Title compound was obtained as an off-white solid in 10% yield. ¹H NMR(300 MHz, CD₃OD): δ=7.50 (s, 21H), 7.25 (d, J=8.4, 1H), 7.14 (m, 2H),7.07 (m, 4H), 6.93 (t, J=7.5, 1H), 6.83 (m, 2H), 6.78 (d, J=7.7, 1H),5.97 (q, J=6.7, 1H), 5.40 (dd, J1=4.6, J2=13.0, 1H), 5.05 (d, J=17.6,1H), 4.49 (m, 3H), 4.42 (s, 2H), 4.30 (m, 3H), 3.37 (m, 1H), 3.24 (m,1H), 2.99 (m, 2H), 1.93 (m, 2H), 1.76 (m, 2H), 1.70 (d, J=7.3, 3H). MSm/e (M+H)⁺=578.1.

EXAMPLE 12

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(9-benzyl-4-chloro-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-amide.N,N′-Disuccinimidyl carbonate (63 mg, 0.25 mmol) was added to a mixtureof7-(R)-Amino-9-(2-morpholin-4-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one(120 mg, 0.24 mmol) and triethylamine (500 μL, 3.6 mmol) indichloromethane (5 mL). Reaction was stirred at room temperature for 30minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine (54 mg,0.23 mmol) was added to the reaction mixture. Reaction was stirred untiljudged complete by HPLC (0.5 hours). Mixture was washed successivelywith water (2×5 mL) and brine (5 mL). Organic layer was concentrated invacuo. Residue was purified by C18 preparatory HPLC(acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed fromthe product containing fractions in vacuo. Remaining aqueous was madebasic with sodium bicarbonate. Mixture was extracted with ethyl acetate(2×20 mL). Combined extracts were washed with brine (10 mL). Organic wasdried (magnesium sulfate), filtered and concentrated. Desired productwas obtained as a white solid in 24% yield. ¹H NMR (500 MHz, CD₃OD):δ=7.91 (s, 1H), 7.16 (m, 4H), 7.10 (d, J=7.3, 1H), 7.04 (m, 3H), 6.92(t, J=7.5, 1H), 6.79 (d, J=7.9, 1H), 5.45 (dd, J1=4.4, J2=13.3, 1H),5.29 (d, J=16.8, 1H), 4.99 (d, J=14.7, 1H), 4.60 (m, 2H), 4.49 (m, 3H),4.39 (s, 2H), 4.28 (t, J=12.7, 2H), 3.36 (m, 1H), 3.19 (dd, J1=14.0,J2=16.2, 1H), 2.98 (m, 2H), 1.91 (m, 2H), 1.71 (m, 2H). MS m/e(M+H)⁺=598.1.

EXAMPLE 13

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(4-trifluoromethyl-benzyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.7-Amino-9-(4-trifluoromethyl-benzyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-8-onebismethanesulfonate was reacted in a manner analogous to the preparationof 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.Title compound was obtained as a white solid in 19% yield. ¹H NMR (500MHz, DMSO-D₆): δ=9.19 (s, 1H), 8.09 (s, 1H), 7.48 (d, J=7.9, 1H), 7.38(d, J=8.4, 1H), 7.34 (d, J=8.5, 1H), 7.10 (m, 3H), 6.85 (t, J=7.0, 1H),6.77 (d, J=7.9, 1H), 6.66 (d, J=6.4, 1H), 5.35 (m, 2H), 4.71 (m, 3H),4.36 (m, 2H), 4.29 (s, 2H), 4.18 (d, J=12.8, 2H), 3.29 (m, 1H), 3.13(dd, J1=13.6, J2=16.6, 1H), 2.81 (m, 2H), 1.72 (m, 2H), 1.56 (d, J=11.3,2H). MS m/e (M+H)⁺=632.1.

EXAMPLE 14

′H-spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one-1-carboxylic acid[8-oxo-9-(4-trifluoromethyl-benzyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.7-Amino-9-(4-trifluoromethyl-benzyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-8-onebismethanesulfonate was reacted in a manner analogous to the preparationof ¹H-spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one-1-carboxylic acid[9-(2-morpholin-4-yl-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.The title compound was obtained as a white solid in 6% yield. ¹H NMR(500 MHz, CD₃OD): δ=7.91 (s, 1H), 7.46 (d, J=8.2, 1H), 7.35 (d, J=8.6,1H), 7.30 (m, 5H), 7.17 (m, 2H), 7.01 (t, J=7.6, 1H), 6.84 (d, J=8.2,1H), 5.51 (dd, J1=4.6, J2=13.1, 1H), 5.40 (d, J=17.1, 1H), 5.07 (d,J=15.3, 1H), 4.64 (d, J=4.9, 1H), 4.61 (s, 1H), 4.43 (s, 1H), 4.09 (m,2H), 3.42 (m, 3H), 3.35 (m, 1H), 3.22 (m, 1H), 2.16 (m, 1H), 2.07 (m,1H), 1.92 (d, J=13.4, 2H). MS m/e (M+H)⁺=618.1.

EXAMPLE 15

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(9-isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-amide.7-(R)-Amino-9-isopropyl-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethanesulfonate was reacted in a manner analogous to the preparationof 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.The desired product was obtained as light yellow solid in 28% yield. ¹HNMR (400 MHz, DMSO-D₆): δ=9.21 (s, 1H), 8.45 (s, 1H), 7.37 (d, J=8.6,1H), 7.10 (m, 3H), 6.86 (m, 1H), 6.77 (d, J=7.6, 1H), 6.56 (m, 1H), 5.26(m, 1H), 5.00 (d, J=17.1, 1H), 4.74 (m, 2H), 4.65 (d, J=17.4, 1H), 4.36(m, 1H), 4.29 (s, 2H), 4.15 (m, 2H), 3.25 (dd, J1=3.7, J2=16.9, 1H),3.04 (dd, J1=13.6, J2=16.5, 1H),2.80 (m, 2H), 1.71 (m, 2H), 1.57 (d,J=11.7, 2H), 1.23 (d, J=6.9, 3H), 0.80 (d, J=6.9, 3H). MS m/e(M+H)⁺=516.4.

EXAMPLE 16

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[9-(3,3-dimethyl-butyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.7-(R)-Amino-9-(3,3-dimethyl-butyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-onebismethanesulfonate was reacted in a manner analogous to the preparationof 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.The desired product was obtained as an off-white solid in 29% yield. ¹HNMR (500 MHz, DMSO-D₆): δ=9.19 (s, 1H), 8.32 (s, 1H), 7.38 (d, J=8.6,1H), 7.10 (t, J=9.2, 3H), 6.86 (t, J=7.5, 1H), 6.77 (d, J=7.6, 1H), 6.53(s, 1H), 5.24 (d, J=16.5, 2H), 4.62 (d, J=17.9, 1H), 4.35 (m, 1H), 4.29(s, 2H), 4.14 (m, 2H), 3.57 (m, 1H), 3.36 (m, 1H), 3.26 (dd, J1=2.8,J2=17.1, 1H), 3.01 (m, 1H), 2.80 (t, J=12.4, 2H), 1.72 (m, 2H), 1.56 (d,J=11.3, 2H), 1.27 (m, 1H), 1.15 (m, 1H), 0.79 (s, 9H). MS m/e(M+H)⁺=558.2.

EXAMPLE 17

4-(8-Oxo-7-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-6,7,8,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylicacid tert-butyl ester.4-(7-(R)-Amino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylicacid tert-butyl ester acetate was reacted in a manner analogous to thepreparation of4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.C18 preparatory HPLC gave the desired product as an off-white solid in26% yield. ¹H NMR (500 MHz, DMSO-D₆): δ=9.22 (s, 1H), 8.38 (s, 1H), 7.38(d, J=8.6, 1H), 7.10 (m, 3H), 6.85 (m, 1H), 6.75 (d, J=7.6, 1H), 6.57(s, 1H), 5.28 (m, 1H), 5.02 (d, J=17.1, 1H), 4.66 (d, J=17.1, 1H), 4.46(m, 1H), 4.34 (m, 1H), 4.30 (s, 2H), 4.08 (m, 4H), 3.76 (m, 1H), 3.25(d, J=17.4, 1H), 3.04 (m, 1H), 2.79 (m, 4H), 1.91 (m, 1H), 1.68 (n, 2H),1.54 (m, 4H), 1.39 (s, 9H). MS m/e (M+H)⁺=679.3.

EXAMPLE 18

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(8-oxo-9-piperidin-4-yl-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-amide.Trifluoroacetic acid (250 μL) was added to a chilled (water ice bath)solution of4-(8-oxo-7-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-6,7,8,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylicacid tert-butyl ester (60 mg, 0.08 mmol) in dichloromethane (1 mL).Reaction was stirred at 0° C. for 1 hour. Mixture was concentrated invacuo. The desired product was obtained as alight yellow solid in 65%yield. ¹H NMR (500 MHz, DMSO-D₆): δ=9.23 (s, 1H), 8.32 (s, 1H), 7.41 (d,J=8.6, 1H), 7.11 (m, 3H), 6.86 (t, J=7.5, 1H), 6.76, d, J=7.9, 1H), 6.62(d, J-6.7, 1H), 5.29 (m, 1H), 5.11 (d, J=16.8, 1H), 4.66 (t, J=1H), 4.53(d, J=17.4, 1H), 4.35 (m, 1H), 4.29 (s, 2H), 4.16 (d, J=12.5, 4H), 3.42(d, J=11.9, 1H), 3.26 (dd, J1=3.8, J2=16.3, 1H), 3.16 (d, J=10.7, 1H),3.05 (m, 2H), 2.83 (m, 3H), 2.15 (m, 1H), 1.70 (m, 4H), 1.57 (d, J=10.7,2H). MS m/e (M+H)⁺=557.2.

EXAMPLE 19

9-(2,2-Dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (62 mg, 0.16 mmol) was added to a solution of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid (45 mg, 0.14 mmol) and N,N-diisopropylethylamine (100 μL, 0.57mmol) in DMF (1.5 mL). Mixture was stirred at room temperature for 45minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine (40 mg,0.17 mmol) was then added to the mixture. Reaction was stirred at roomtemperature until it was judged complete by HPLC (45 minutes). C18Preparatory HPLC (acetonitrile-water-trifluorocacetic acid) wasperformed on the crude mixture. Acetonitrile was removed from thefractions containing the desired product in vacuo. Remaining aqueous wasmade basic with sodium bicarbonate. Mixture was extracted with ethylacetate (2×15 mL). Combined extracts were washed with saturated aqueoussodium bicarbonate (10 mL). Organic was dried (magnesium sulfate),filtered and concentrated in vacuo. Title compound was obtained as awhite solid in 50% yield. ¹H NMR (500 MHz, DMSO-D₆): δ=9.23 (s, 1H),8.23 (s, 1H), 7.37 (d, J=8.5, 1H), 7.10 (m, 3H), 6.86 (t, J=7.3, 1H),6.77 (d, J=7.9, 1H), 5.38 (d, J=16.2, 1H), 4.63 (d, J=17.4, 1H), 4.50(m, 1H), 4.40 (m, 1H), 4.28 (s, 2H), 4.09 (m, 1H), 3.87 (m, 1H), 3.55(t, J=13.0, 1H), 3.10 (m, 2H), 3.01 (m, 3H), 2.88 (m, 1H), 2.59 (m, 1H),2.34 (m 1H), 1.84 (m, 1H), 1.59 (m, 3H), 0.74 (d, J=19.2, 9H). MS m/e(M+H)⁺=543.2.

EXAMPLE 20

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.Methanesulfonic acid (250 μL) was added to a solution of[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamicacid benzyl ester (90 mg, 0.20 mmol) and anisole (70 μL, 0.64 mmol) indichloromethane (2 mL). Reaction stirred at room temperature for 2hours. Mixture was diluted with diethyl ether (40 mL). Mixture wasallowed to stand at room temperature for 30 minutes. Solvents weredecanted off. Residue was washed with diethyl ether (30 mL) then driedin vacuo. Residue was dissolved in a mixture of triethlyamine (250 μL,1.8 mmol) in dicloromethane (5 mL). N,N′-Disuccinimidyl carbonate (61mg, 0.24 mmol) was added to the mixture. Reaction was stirred at ambienttemperature for 30 minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine (55 mg, 0.24 mmol) was then added to the mixture. Reactionwas stirred at ambient temperature for 30 minutes. Mixture was washedsuccessively with water (2×5 mL) and brine (5 mL). Organic was dried(magnesium sulfate), filtered and concentrated. C18 Preparatory HPLC(acetonitrile-water-trifluoroacetic acid) was preformed on the residue.Acetonitrile was removed from the product containing fractions in vacuo.Remaining aqueous was made basic with sodium bicarbonate. Mixture wasextracted with ethyl acetate (2×15 mL). Combined extracts were dried(magnesium sulfate), filtered and concentrated in vacuo. Title compoundwas obtained as a white solid in 37% yield. ¹H NMR (500 MHz, CD₃OD):δ=8.26 (s, 1H), 7.26 (s, 1H), 7.13 (m, 3H), 6.93 (t, J=7.5, 1H), 6.78(d, J=7.9, 1H), 5.44 (d, J=17.1, 1H), 5.34 (dd, J1=3.5, J2=13.0, 1H),4.70 (d, J=17.4, 1H), 4.47 (m, 1H), 4.40 (s, 2H), 4.26 (m, 2H), 3.82 (d,J=13.4, 1H), 3.19 (m, 1H), 3.08 (d, J=13.7, 1H), 2.94 (m, 2H), 1.90 (m,2H), 1.71 (d, J=12.2, 2H), 0.81 (s, 9H). MS m/e (M+H)⁺=578.3.

EXAMPLE 21

4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(90 mg, 0.28 mmol) was added to a solution of[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid (85 mg, 0.23 mmol) and N,N-diisopropylethyl amine (100 μL, 0.57mmol) in DMF (3 mL). Mixture was stirred at ambient temperature for 15minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine (65 mg,0.28 mmol) was then added to the mixture. Reaction was stirred atambient temperature for 1 hour. Mixture was diluted with ethyl acetate(20 mL). Mixture was washed successively with water (2×15 mL), and brine(10 mL). Organic was dried (magnesium sulfate), filtered andconcentrated in vacuo. Residue was purified by C18 preparatory HPLC(acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed fromthe product containing fractions in vacuo. Remaining aqueous was madebasic with sodium bicarbonate. Mixture was extracted with ethyl acetate(2×20 mL). Combined extracts were washed with brine (10 mL). Organic wasdried (magnesium sulfate), filtered and concentrated in vacuo. Titlecompound was obtained as a white solid in 37% yield. ¹H NMR (500 MHz,DMSO-D₆): δ=13.55 (s, 1H), 9.21 (s, 1H), 8.36 (s, 1H), 7.25 (s, 1H),7.09 (m, 2H), 6.86 (t J=7.3, 1H), 6.77 (d, J=7.9, 1H), 5.36 (d, J=15.6,1H), 4.63 (d, J=17.1, 1H), 4.51 (m, 1H), 4.40 (m, 1H), 4.29 (s, 2H),4.10 (d, J=13.2, 1H), 3.87 (m, 1H), 3.57 (m, 1H), 3.11 (m, 2H), 3.00 (m,2H), 2.88 (m, 1H), 2.59 (m, 1H), 2.32 (m, 1H), 1.85 (m, 1H), 1.59 (m,3H), 0.74 (d, J=18.3, 9H). MS m/e (M+H)⁺=577.0.

EXAMPLE 22

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl]-amide.In a manner similar to4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide,the title compound was prepared by reacting(7R)-7-amino-9-(2,2-dimethyl-propyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one,dihydrochloride with 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one,hydrochloride to give the title compound (80% yield). MS (ESI) 544(M+H); R_(f)=1.51.

EXAMPLE 23

N-[9-(2,2-dimethylpropyl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]-2′-oxo-2′,3′dihydro-1H,1′H-spiro[piperidine-4,4′-quinazoline]-1-carboxamide. In a mannersimilar to4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide,the title compound was prepared by reacting(7R)-7-Amino-9-(2,2-dimethyl-propyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one,dihydrochloride with 1′H-spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one,hydrochloride to give the title compound (80% yield). MS (ESI) 530(M+H); R_(f)=1.44.

EXAMPLE 24

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(9-isobutyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-amide.In a manner similar to4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide,the title compound was prepared by reacting(7R)-7-amino-9-isobutyl-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one,dihydrochloride with 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one,hydrochloride to give the title compound (80% yield). MS (ESI) 530(M+H); R_(f)=1.41.

EXAMPLE 25

N-[9-(2-methylpropyl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]-2′-oxo-2′,3′-dihydro-1H,1′H-spiro[piperidine-4,4′-quinazoline]-1-carboxamide. In a mannersimilar to4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide,the title compound was prepared by reacting(7R)-7-amino-9-isobutyl-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one,dihydrochloride with 1′H-spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one,hydrochloride to give the title compound (80% yield). MS (ESI) 516(M+H); R_(f)=1.35.

EXAMPLE 26

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-pyridin-4-yl-ethyl)-3,6,7,8,9,10-hexahydro-2, 3,9-triaza-cyclohepta[e]inden-7-yl]-amide. In a manner similar to4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide,the title compound was prepared by reacting(7R)-7-amino-9-(2-pyridin-4-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one,dihydrochloride with 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one,hydrochloride to give the title compound (80% yield). MS (ESI) 530(M+H); R_(f)=1.41.

EXAMPLE 27

N-[9-(2-pyridin-4-yl-ethyl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]-2′-oxo-2′,3′-dihydro-1H,1′H-spiro[piperidine-4,4′-quinazoline]-1-carboxamide.In a manner similar to4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide,the title compound was prepared by reacting(7R)-7-amino-9-(2-pyridin-4-yl-ethyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one,dihydrochloride with 1′H-spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one,hydrochloride to give the title compound (80% yield). MS (ESI) 516(M+H); R_(f)=1.35.

EXAMPLE 28

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(8-oxo-9-pyridin-4-ylmethyl-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-amide.In a manner similar to4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide,the title compound was prepared by reacting(7R)-7-amino-9-pyridin-4-ylmethyl-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one,dihydrochloride with 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one,hydrochloride to give the title compound (80% yield). MS (ESI) 565(M+H); R_(f)=1.09.

EXAMPLE 29

N-[9-pyridin-4-ylmethyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]-2′-oxo-2′,3′-dihydro-1H,1′H-spiro[piperidine-4,4′-quinazoline]-1-carboxamide.In a manner similar to4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide,the title compound was prepared by reacting(7R)-7-amino-9-pyridin-4-ylmethyl-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one,dihydrochloride with 1′H-spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one,hydrochloride to give the title compound (80% yield). MS (ESI) 551(M+H); R_(f)=1.07.

EXAMPLE 30

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(4,9-dimethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-amide.To a solution of(4,9-dimethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamicacid benzyl ester (50 mg, 0.132 mmol) in methanol and chloroform (0.5mL) was added 10% palladium on carbon (20 mg) under nitrogen atmosphere.The reaction mixture was brought to hydrogen atmosphere (1 atm) andstirred for 3 h. The catalyst was filtered and the solvent wasevaporated to give7-amino-4,9-dimethyl-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one,hydrochloride in almost quantitative yield. To the amine salt indichloromethane was added disuccinimidyl carbonate (37 mg, 0.145 mmol)and triethylamine (0.11 mL, 0.8 mmol) at room temperature. After 120min, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one, hydrochloride (39mg, 0.145 mmol) was added and stirring continued for 12 h. The solventwas evaporated and the crude product was purified by Prep HPLC to give4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(4,9-dimethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-amidein 59% overall yield. MS (ESI) 502 (M+H); R_(f)=1.31.

EXAMPLE 31

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide.To a stirred solution of(8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-carbamicacid tert-butyl ester (300 mg, 0.76 mmol) in dichloromethane (2 mL) wasadded a 4.0 M solution of hydrogen chloride in dioxane (15 mL). Thereaction mixture was stirred and removed the solvent to give the aminesalt in quantitative yield. The amine salt was dissolved indichloromethane (20 mL) followed by addition of N,N′-disuccinimidylcarbonate (214 mg, 0.83 mmol) and triethylamine (0.64 mL, 4.6 mmol).After 15 min, 3-piperidin-4-yl-3,4-dihydro-1H-quinazolin-2-one,hydrochloride (225 mg, 0.84 mmol) was added and stirring continued for12 h. The reaction mixture was then washed with aqueous sodiumhydrogencarbonate, 1.0 M hydrochloric acid and dried (Na₂SO₄). The crudeproduct was purified by flash chromatography using 5% methanol indichloromethane to give4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amidein 66% yield. MS (ESI) 554 (M+H); R_(f)=1.67.

EXAMPLE 32

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide.To a stirred solution of4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(8-benzyloxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide(187 mg, 0.34 mmol) in methanol (30 mL) followed by 10% palladium oncarbon (30 mg) under nitrogen. The reaction mixture was brought to 1atmosphere of hydrogen and stirred for 12 h. The catalyst was filteredand the solvent was evaporated to give4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amidein quantitative yield.

MS (ESI) 464 (M+H); R_(f)=1.34.

EXAMPLE 33

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(7,9-dichloro-8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide.To a stirred solution of4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide(27 mg, 0.058 mmol) in dichloromethane (10 mL) was added methanol (2mL), ether (3 mL) followed by sulfuryl chloride (70 μL) at roomtemperature. The reaction mixture was stirred for additional 12 h andthen concentrated. The crude product was purified by Prep HPLC to give4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(7,9-dichloro-8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amidein 58% yield. MS (ESI) 532 (M+H); R_(f)=1.40.

EXAMPLE 34

4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(7,9-dibromo-8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide.To a stirred solution of4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amide(39 mg, 0.084 mmol) in dichloromethane (10 mL) was addeddiisopropylamine (0.06 mL, 0.42 mmol) followed by N-bromosuccinimide (33mg, 0.185 mmol) at room temperature. The reaction mixture was stirredfor additional 1 h and then the solvent was removed. The crude productwas purified by Prep HPLC to give4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(7,9-dibromo-8-hydroxy-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-amidein 74% yield. MS (ESI) 620 (M+H); R_(f)=1.45.

EXAMPLE 35

(S)-4-Chloro-7-(2-oxo-2-(4-(5-phenyl-1H-pyrazol-3-yl)piperidin-1-yl)ethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(S)-2-(4-chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9, 10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid dihydrochloride (66mg, 0.23 mmol) and 4-(5-phenyl-1H-pyrazol-3-yl)piperidine hydrochloride(40 mg, 0.15 mmol) were reacted following a procedure analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound (34 mg) was obtained as white solid. MS (ESI) 594 (M+H);R_(f)=1.99.

EXAMPLE 36

(S)-9-Neopentyl-7-(2-oxo-2-(4-(2-oxo-4-phenyl-2,3-dihydroimidazol-1-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (62 mg, 0.16 mmol) was added to a solution of[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid (50 mg, 0.16 mmol) and N,N-diisopropylethylamine (85 μL, 0.48 mmol)in DMF (2.0 mL). Mixture was stirred at room temperature for 45 minutes.4-phenyl-1-(piperidin-4-yl)-1H-imidazol-2(3H)-one hydrochloride (53 mg,0.19 mmol) was then added to the mixture. The desired compound waspurified by prep HPLC. The title compound (49 mg) was obtained as awhite foam. MS (ESI) 555 (M+H); R_(f)=1.54.

EXAMPLE 37

(R)-N-(8-Benzyl-7-oxo-1,5,6,7,8,9-hexahydroazepino[4,3-f]indazol-6-yl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide.(R)-Benzyl1-acetyl-8-benzyl-7-oxo-1,5,6,7,8,9-hexahydroazepino[4,3-f]indazol-6-ylcarbamate(52 mg, 0.11 mmol) was dissolved in a mixture of methanol (7 mL) andacetic acid (100 μL). A catalytic amount of 10% palladium on carbon wasadded to the mixture. Reaction was placed on a Parr apparatus under 60psi of hydrogen gas. Reaction shook at room temperature for 2 hours.Mixture was filtered. Filtrate was concentrated. Residue was dissolvedin dichloromethane (5 mL). Aqueous sodium bicarbonate (5 mL) was addedto the mixture. 20% Phosgene in toluene (62 μL, 0.12 mmol) was added tothe mixture with vigorous stirring. Reaction was stirred vigorously atroom temperature for 20 minutes.4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidinium acetate was addedto the mixture. Reaction stirred at room temperature for 1 hour. Layerswere partitioned. Organics were washed twice with 1N hydrochloric acidand once with brine. Organic layer was dried (magnesium sulfate),filtered and concentrated in vacuo. Residue was dissolved in methanol (5mL). Potassium carbonate (20 mg, 0.14 mmol) was added to the mixture.Reaction stirred at room temperature for 1 hour. Reaction was quenchedwith trifluoroacetic acid. Mixture was purified by prep HPLC. Titlecompound was obtained as a white solid in 11% yield. MS m/e(M+H)⁺=564.3. R_(f)=1.89 min.

EXAMPLE 38

(S)-9-Benzyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.Title compound was prepared in a manner analogous to the preparation of4-chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid in 18% yield. MS m/e (M+H)⁺=563.1.¹H NMR (500 MHz, DMSO-D₆): δ=12.93 (s, 1H), 9.23 (d, J=6.71, 1H), 8.05(d, J=10.38, 1H), 7.33 (d, J=8.55, 1H), 7.13 (m, 7H), 6.99 (d, J=7.63,1H), 6.84 (m, 1H), 6.76 (m, 1H), 5.34 (d, J=17.4, 1H), 4.62 (m, 4H),4.41 (m, 1H), 4.27 (d, J=22.89, 2H), 4.11 (d, J=12.82, 1H), 3.99 (m,1H), 3.14 (d, J=15.87, 2H), 3.07 (m, 1H), 2.61 (m, 1H), 2.42 (m, 1H),1.84 (m, 1H), 1.62 (m, 3H).

EXAMPLE 39

(S)-7-(2-(4-(8-Fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)-2-oxoethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.Title compound was prepared in a manner analogous to the preparation of9-(2,2-Dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid in 35% yield. MS m/e (M+H)⁺=561.3.¹H NMR (500 MHz, DMSO-D₆): δ=13.00 (s, 1H), 9.24 (s, 1H), 8.22 (s, 1H),7.37 (d, J=8.54, 1H), 7.11 (d, J=7.63, 7H), 7.05 (m, 1H), 6.94 (m, 1H),6.88 (m, 1H), 5.38 (d, J=17.09, 1H), 4.62 (d, J=17.09, 1H), 4.51 (m,1H), 4.40 (m, 1H), 4.35 (s, 2H), 4.10 (d, J=13.43, 2H), 3.88 (m, 1H),3.55 (t, J=12.67, 1H), 3.11 (m, 2H), 3.01 (m, 2H), 2.87 (m, 1H), 2.60(m, 1H) 2.34 (m, 1H), 1.84 (m, 1H), 1.61 (m, 3H), 0.74 (d, J=17.70, 9H).

EXAMPLE 40

(S)-4-Chloro-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)-2-oxoethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.Title compound was prepared in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid in 49% yield. MS m/e (M+H)⁺=595.2.¹H NMR (500 MHz, DMSO-D₆): δ=13.55 (s, 1H), 9.24 (s, 1H), 8.37 (s, 1H),7.37 (d, J=8.54, 1H), 7.24 (s, 1H), 7.05 (m, 1H), 6.96 (m, 1H), 6.88(dd, J1=12.21, J2=7.32, 1H), 5.36 (d, J=18.01, 1H), 4.63 (d, J=17.09,1H), 4.50 (m, 1H), 4.42 (m, 1H), 4.35 (s, 2H), 4.10 (d, J=12.51, 1H),3.88 (m, 1H), 3.57 (m, 1H), 3.09 (d, J=15.56, 2H), 3.00 (m, 2H), 2.88(t, J=13.12, 1H), 2.60 (m, 1H) 2.33 (d, J15.26, 1H), 1.85 (m, 1H), 1.60(m, 3H), 0.73 (d, J=17.09, 9H).

EXAMPLE 41

(S)-4-Chloro-9-neopentyl-7-(2-oxo-2-(4-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.Title compound was prepared from2-(piperidin-4-yl)-1,2-dihydroisoquinolin-3(4H)-one hydrochloride in amanner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as yellow solid in 35% yield. MS m/e (M+H)⁺=576.2.¹H NMR (500 MHz, DMSO-D₆): δ=13.55 (s, 1H), 8.37 (s, 1H), 7.29 (s, 1H ),7.23 (dd, J1=7.63, J2=6.10, 4H), 5.37 (dd, J1=16.48, J2=7.63, 1H), 4.64(d, J=17.70, 2H), 4.48 (s, 1H), 4.38 (s, 2H), 4.09 (m, 1H), 3.57 (m,1H), 3.54 (s, 2H), 3.11 (m, 3H), 3.00 (m, 2H), 2.89 (m, 1H), 2.61 (m,1H), 2.36 (m, 1H), 1.54 (m, 2H), 0.74 (d, J=28.08, 9H).

EXAMPLE 42

(S)-9-Neopentyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.Title compound was prepared from 3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride in a manner analogous to the preparation of9-(2,2-Dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid in 31% yield. MS m/e (M+H)⁺=540.2.¹H NMR (500 MHz, DMSO-D₆): δ=11.76 (s, 1H), 8.22 (s, 1H), 7.70 (d,J=8.85, 1H), 7.62 (s, 1H), 7.43 (t, J=7.48, 1H), 7.37 (d, J=8.55, 1H),7.28 (d, J=8.24, 1H), 7.15 (t, J=7.32, 1H) 7.11 (d, J=8.55, 1H), 5.38(d, J=17.09, 1H), 4.62 (d, J=16.79, 1H), 4.55 (d, J=11.29, 1H), 4.13 (s,1H), 3.88 (s, 1H), 3.58 (s, 2H), 3.16 (m, 2H), 3.07 (m, 3H), 2.88 (t,J=14.34, 1H), 2.64 (m, 1H), 2.36 (m, 1H), 1.92 (d, J=10.38, 1H), 1.84(d, J=11.29, 1H), 1.57 (m, 1H), 1.40 (m, 1H), 0.73 (s, 9H).

EXAMPLE 43

(S)-4-Chloro-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.Title compound was prepared from 3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as off-white solid in 46% yield. MS m/e(M+H)⁺=574.2. ¹H NMR (500 MHz, DMSO-D₆): δ=13.54 (s, 1H), 11.76 (s, 1H),8.36 (s, 1H), 7.70 (d, J=5.80, 1H), 7.61 (d, J=7.63, 1H), 7.43 (t,J=7.63, 1H), 7.28 (d, J=7.93, 1H), 7.24 (s, 1H), 7.15 (t, J=7.32, 1H),5.37 (d, J=17.09, 1H), 4.63 (d, J=16.79, 1H), 4.55 (d, J=12.21, 1H),4.13 (m, 1H), 3.87 (m, 1H), 3.58 (d, J=13.12, 1H), 3.15 (m, 2H), 3.03(m, 3H), 2.88 (m, 1H), 2.63 (m, 1H),2.34(d, J=16.17 1H), 1.91 (d,J=1.22, 1H), 1.84 (d, J=11.29, 1H), 1.57 (m, 1H), 1.40 (m, 1H), 0.72 (s,9H).

EXAMPLE 44

(S)-4-Chloro-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-4-phenyl-2,3-dihydroimidazol-1-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.Title compound was prepared from4-phenyl-1-(piperidin-4-yl)-1H-imidazol-2(3H)-one in a manner analogousto the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid in 46% yield. MS m/e (M+H)⁺=589.2.¹H NMR (500 MHz, DMSO-D₆): δ=13.55 (s, 1H), 10.68 (s, 1H), 8.37 (s, 1H),7.50 (d, J=7.63, 2H), 7.32 (t, J=7.02, 2H), 7.24 (s, 1H), 7.16 (m, 2H),5.37 (d, J=14.34, 1H), 4.63 (d, J=16.79, 1H), 4.51 (t, J=10.83, 1H),4.13 (m, 2H), 3.89 (m, 1H), 3.57 (m, 1H), 3.18 (m, 1H), 3.03 (m, 3H),2.89 (t, J-15.1 1, 1H), 2.66 (m, 1H), 2.34 (d, J=16.17 1H), 1.84 (m,3H), 1.60 (m, 1H), 0.73 (d, J=13.73, 9H).

EXAMPLE 45

(S)-4-Chloro-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-4-(pyridin-2-yl)-2,3-dihydroimidazol-1-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.Title compound was prepared from1-(piperidin-4-yl)-4-(pyridine-2-yl)-1H-imidazol-2(3H)-one in a manneranalogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid in 37% yield. MS m/e (M+H)⁺=590.2.¹H NMR (500 MHz, DMSO-D₆): δ=13.54 (s, 1H), 10.69 (d, 1H), 8.45 (s, 1H),8.37 (s, 1H), 7.74 (s, 1H), 7.54 (d, J=8.24, 1H), 7.33 (d, J=4.88, 1H),7.25 (s, 1H), 7.15 (dd, J1=6.71, J2=5.19, 1H), 5.37 (d, J=17.09, 1H),4.63 (d, J=15.87, 1H), 4.50 (s, 1H), 4.12 (m, 2H), 3.87 (m, 1H), 3.56(dd, J1=28.69, J2=13.43, 1H), 3.18 (t, J=$$ 13.73, 1H), 3.10 (d,J=14.65, 1H), 3.01 (m, 2H), 2.88 (t, J=15.26, 1H), 2.66 (m, 1H), 2.35(d, J=14.95, 1H), 1.84 (m, 3H), 1.57 (m, 1H), 0.73 (d, J=16.17, 9H).

EXAMPLE 46

(S)-4-Chloro-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-1′H-spiro(piperidine-4,4′-quinazoline)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.Title compound was prepared from1′H-spiro(piperidine-4,4′)quinazolin)-2′(3′H)-one in a manner analogousto the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid in 37% yield. MS m/e (M+H)⁺=563.2.¹H NMR (500 MHz, DMSO-D₆): δ=13.54 (s, 1H), 9.22 (d, J=10.68, 1H), 8.36(s, 1H), 7.30 (m, 2H), 7.24 (s, 1H), 7.12 (m, 1H), 6.85 (m, 2H), 5.36(d, J=16.78, 1H), 4.62 (dd, J1=16.94, J2=9.31, 1H), 4.26 (t, J=14.34,1H), 3.89 (m, 2H), 3.63 (m, 1H), 3.52 (m, 1H), 3.09 (m, 3H), 2.98 (m,1H), 2.88 (m, 1H), 2.33 (dd, J1=51.12, J2=15.72, 1H), 1.96 (m, 1H), 1.74(m, 3H), 0.74 (d, J=16.48, 9H).

EXAMPLE 47

(S)-4-Chloro-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.Title compound was prepared from8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride in a manneranalogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid in 36% yield. MS m/e (M+H)⁺=592.2.¹H NMR (500 MHz, DMSO-D₆): δ13.54 (s, 1H), 11.78 (s, 1H), 8.36 (s, 1H),7.76 (d, J=5.19, 1H), 7.46 (d, J=7.93, 1H), 7.34 (dd, J1=0.53, J2=8.70,1H), 7.24 (s, 1H), 7.14 (m, 1H), 53.6 (d, J=16.48, 1H), 4.63 (d,J=17.40, 1H), 4.55 (d, J=11.29, 1H), 4.12 (m, 1H), 3.87 (m, 1H), 3.58(d, J=13.12, 1H), 3.17 (m, 1H), 3.05 (m, 4H), 2.88 (m, 1H), 2.65 (m,1H), 2.34 (d, J=15.87 1H), 1.92 (d, J=12.51, 1H, 1.84 (d, J=11.29, 1H),1.57 (m, 1H), 1.40 (m, 1H), 0.72 (s, 9H).

EXAMPLE 48

(S)-4-Chloro-9-neopentyl-7-(2-oxo-2-(4-(3-oxo-3,4-dihydroquinoxalin-2-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.Title compound was prepared from 3-(piperidin-4-yl)quinoxalin-2(1H)-onehydrochloride in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid in 49% yield. MS m/e (M−H)⁻=573.2.¹H NMR (500 MHz, DMSO-D₆): δ=13.53 (s, 1H), 12.35 (s, 1H), 8.36 (s, 1H),7.72 (t, J=8.70, 1H), 7.48 (t, J=7.78, 1H), 7.28 (m, 2H), 7.24 (s, 1H),5.37 (d, J=17.09, 1H), 4.63 (d, J=17.09, 1H), 4.49 (m, 1H), 4.12 (m,1H), 3.86 (m, 1H), 3.59 (t, J=12.36, 1H), 3.45 (m, 1H), 3.22 (m, 1H),3.10 (m, 1H), 2.99 (m, 1H), 2.87 (dd, J1=15.56, J2=14.34, 1H), 2.72 (m,1H), 2.36 (m, 1H), 1.96 (d, J=12.82, 1H), 1.89 (d, J=13.12, 1H), 1.70(m, 1H), 1.52 (m, 1H), 0.72 (s, 9H).

EXAMPLE 49

(S)-4-Chloro-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)ethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid dihydrochloride (90 mg, 0.23 mmol) and4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine hydrochloride (75mg, 0.28 mmol) were reacted following a procedure analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 27% yield. MS m/e(M+H)⁺=598.2. ¹H NMR (500 MHz, DMSO-D₆): δ=13.47 (s, 1H), 9.19 (s, 1H),8.31 (s, 2H), 8.23 (s, 1H), 7.22 (s, 1H), 7.12 (s, 3H), 6.99 (m, 1H),6.84 (m, 2H), 6.77 (s, 1H), 5.40 (d, J=15.26, 1H), 4.65 (m, 3H), 4.54(d, J=10.38, 1H), 4.40 (m, 1H), 4.30 (s, 1H), 4.22 (s, 1H), 4.09 (m,1H), 3.99 (m, 1H), 3.14 (m, 2H), 3.03 (m, 1H), 2.93 (m, 1H), 2.60 (m,1H), 1.78 (m, 1H), 1.58 (m, 3H).

EXAMPLE 50

(S)-4-Chloro-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)-2-oxoethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid dihydrochloride (100 mg, 0.2 mmol) and8-fluoro-3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-onehydrochloride (61 mg, 0.2 mmol) were reacted in a manner analogous tothe preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 16% yield. MS m/e(M+H)⁺=616.2. ¹H NMR (500 MHz, DMSO-D₆): δ=13.46 (s, 1H), 9.23 (d,J=6.41, 1H), 8.31 (m, 2H), 8.24 (d, J=6.10, 1H), 7.22 (s, 1H), 7.13 (dd,J1=9.46, J2=4.88, 2H), 7.05 (m, 1H), 6.91 (m, 1H), 6.85 (s, 1H), 5.40(d, J=17.09, 1H), 4.66 (m, 3H), 4.54 (d, J=11.90, 1H), 4.41 (m, 1H),4.36 (s, 1H), 4.28 (d, J=4.58 1H), 4.10 (d, J=12.51, 1H), 4.00 (m, 1H),3.17 (m, 2H), 3.04 (m, 1H), 2.94 (m, 1H), 2.62 (d, J=11.29, 1H), 2.43(m, 1H), 1.83 (m, 1H), 1.62 (m, 3H).

EXAMPLE 51

(S)-4-Chloro-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid dihydrochloride (100 mg, 0.22 mmol) and8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one acetate (90 mg, 0.29 mmol)were reacted following a procedure analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as tan solid in 13% yield. MS rule(M+H)⁺=613.3. ¹H NMR (500 MHz, DMSO-D₆): δ=13.46 (s, 1H), 11.78 (s, 1H),8.30 (s, 2H), 8.23 (s, 1H), 7.75 (d, J=19.53, 1H), 7.45 (m, 1H), 7.34(m, 1H), 7.21 (s, 1H), 7.12 (m, 3H), 5.40 (d, J=16.48, 1H), 4.64 (m,4H), 4.13 (d, J=12.82, 1H), 4.00 (m, 1H), 3.17 (m, 2H), 3.04 (m, 2H),2.94 (m, 1H, 2.67 (m, 1H), 2.44 (m, 1H), 1.94 (m, 1H), 1.86 (m, 1H),1.57 (m, 1H), 1.42 (m, 1H).

EXAMPLE 52

(S)-4-Chloro-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid dihydrochloride (100 mg, 0.23 mmol) and3-(piperidin-4-yl)quinolin-2(1H)-one (55 mg, 0.24 mmol) were reactedfollowing a procedure analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 41% yield. MS m/e(M+H)⁺=595.2. ¹H NMR (500 MHz, DMSO-D₆): δ=13.46 (s, 1H), 11.76 (s, 1H),8.30 (d, J=5.19, 2H), 8.23 (s, 1H), 7.69 (d, J=19.84, 1H), 7.62 (m, 1H),7.44 (m, 1H), 7.28 (d, J=7.93, 1H), 7.21 (s, 1H), 7.14 (m, 3H), 5.40 (d,J=17.09, 1H), 4.65 (m, 3H), 4.13 (d, J=13.43, 1H), 4.01 (m, 1H), 3.17(d, J=14.95, 2H), 3.04 (m, 2H), 2.94 (m, 1H), 2.66 (m, 1H), 2.45 (m,2H), 1.93 (d, J=11.60, 1H), 1.85 (d, J=12.82, 1H), 1.56 (m, 1H), 1.41(m, 1H).

EXAMPLE 53

(S)-4-Chloro-7-(2-oxo-2-(4-(2-oxo-4-phenyl-2,3-dihydroimidazol-1-yl)piperidin-1-yl)ethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(S)-2-(4-Chloro-8-oxo-9-(pyridin-4-ylmethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid dihydrochloride (100 mg, 0.23 mmol) and4-phenyl-1-(piperidin-4-yl)-1H-imidazol-2(3H)-one (60 mg, 0.28 mmol)were reacted following a procedure analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 30% yield. MS m/e(M+H)⁺=610.3. ¹H NMR (500 MHz, DMSO-D₆): δ=13.46 (s, 1H), 10.68 (d,J=4.27, 1H), 8.30 (d, J=3.97, 2H), 8.23 (s, 1H), 7.50 (d, J=7.93, 1H),7.45 (d, J=7.63, 1H), 7.31 (m, 2H), 7.22 (s, 1H), 7.14 (m, 4H), 5.41 (d,J=16.78, 1H), 4.66 (m, 3H), 4.55 (m, 1H), 4.13 (m, 2H), 3.99 (m, 1H),3.33 (m, 1H), 3.18 (m, 1H), 3.05 (dd, J1=16.02, J2=8.70, 1H), 2.94 (m,1H), 2.68 (m, 1H), 2.44 (m, 1H), 1.81 (m, 3H), 1.62 (m, 1H).

EXAMPLE 54

(S)-9-((1H-Imidazol-2-yl)methyl)-4-chloro-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(S)-Methyl2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate(58 mg, 0.15 mmol) was dissolved in a mixture containing methanol (2mL), tetrahydrofuran (2 mL), and water (2 mL). Lithium hydroxidemonohydrate (20 mg, 0.48 mmol) was added to the mixture. Reactionstirred at room temperature for 15 hours. Reaction was quenched with 1Nhydrochloric acid (0.5 mL). Mixture was concentrated in vacuo. Residuewas dissolved in DMF (2 mL). N,N-Diisopropylethylamine was added to themixture followed by o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumTetrafluoroborate (60 mg, 0.19 mmol). Mixture stirred at roomtemperature for 30 minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine hydrochloride (50 mg, 0.19 mmol) was added to the mixture.Reaction stirred at room temperature for 3 hours. Reaction mixture waspurified by preparatory HPLC. Desired fractions were identified.Acetonitrile was removed from the fractions in vacuo. Remaining aqueouswas made basic with sodium bicarbonate. Mixture was extracted twice withethyl acetate. Combined extracts were dried (magnesium sulfate),filtered and concentrated in vacuo. Title compound was obtained as whitesolid in 28% yield. MS m/e (M+H)⁺=587.2. ¹H NMR (500 MHz, DMSO-D₆):δ=13.46 (s, 1H), 11.75 (s, 1H), 9.20 (s, 1H), 8.14 (s, 1H), 7.19 (s,1H), 7.12 (m, 2H), 6.84 (m, 2H), 6.77 (d, J=7.93, 1H), 5.23 (d, J=15.16,1H), 4.76 (m, 1H), 4.69 (dd, J1=15.26, J2=5.19, 1H), 4.53 (d, J=13.43,1H), 4.47 (d, J=15.26, 1H), 4.40 (m, 1H), 4.29 (d, J=3.97, 2H), 4.08 (m,1H), 3.89 (d, J=9.77, 1H), 3.15 (m, 2H), 3.00 (m, 1H), 2.91 (m, 3H),2.60 (m, 1H) 2.44 (m, 2), 1.80 (m, 1H), 1.60 (m, 3H).

EXAMPLE 55

(R)-N-(8-Amino-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamidetrifluoroacetate.(R)-N-(8-Amino-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide(95 mg, 0.15 mmol) was dissolved in dichloromethane (2 mL).Trifluoroacetic acid (1 mL) was added to the mixture. Reaction stirredat room temperature for 1 hour. Mixture was concentrated in vacuo.Residue was purified by preparatory HPLC. Solvent was lyophilized fromthe proper fractions. Title compound was obtained as white solid in 64%yield. MS m/e (M+H)⁺=553.

EXAMPLE 56

(R)-N-(8-Amino-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamidetrifluoroacetate. (R)-tert-Butyl2-benzyl-9-methyl-3-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamido)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamatewas reacted in a manner analogous with the preparation of(R)-N-(8-amino-2-benzyl-7-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamidetrifluoroacetate. Title compound was obtained as off-white solid in 31%yield. MS m/e (M+H)⁺=553.

EXAMPLE 57

N-((R)-9-Benzyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperidine-1-carboxamide.(S)-2-(9-Benzyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid (80 mg, 0.24 mmol) and3-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (75 mg, 0.33 mmol) werereacted in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid in 33% yield. MS m/e (M+H)⁺=542.3.¹H NMR (500 MHz, DMSO-D₆): δ=13.01 (s, 1H), 10.11 (s, 1H), 8.21 (s, 1H),7.36 (d, J=7.93, 1H), 7.17 (m, 1H), 7.11 (m, 2H), 6.91 (m, 1H), 6.83 (d,J=7.63, 1H), 5.35 (d, J=17.09, 1H), 1H), 4.61 (d, J=17.40, 1H), 4.38 (m,1H), 4.02 (m, 1H), 3.83 (s, 1H), 3.55 (t, J=12.36, 1H), 2.95 (m, 6H),2.79 (m, 1H), 2.42 (m, 1H), 2.31 (m, 2H), 1.90 (m, 1H), 1.63 (m, 2H),1.17 (m, 1H), 0.72 (d, J=9.77, 9H).

EXAMPLE 58

(7S)-9-Benzyl-7-(2-oxo-2-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperazin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(S)-2-(9-Benzyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid (80 mg, 0.24 mmol) and3-(piperazin-1-yl)-3,4-dihydroquinolin-2(1H)-one (75 mg, 0.32 mmol) werereacted in a manner analogous to the preparation of4-chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 21% yield. MS m/e(M+H)⁺=543.3. ¹H NMR (500 MHz, DMSO-D₆): δ=13.01 (s, 1H), 10.13 (s, 1H),8.21 (s, 1H), 7.36 (d, J=8.54, 1H), 7.19 (d, J=7.02, 1H), 7.11 (m, 2H),6.90 (t, J=7.32, 1H), 6.82 (d, J=7.93, 1H), 5.36 (d, J=17.40, 1H), 4.61(d, J=17.09, 1H), 3.84 (m, 1H), 3.57 (d, J=13.12, 1H), 3.47 (m, 2H),3.38 (m, 1H), 3.32 (M, 1H), 3.09 (m, 1H), 3.02 (d, J=14.04, 1H), 2.985(m, 2H), 2.85 (m, 1H), 2.75 (m, 1H), 2.65 (m, 3H), 2.50 (m, 2H), 2.31(d, J=16.48, 1H), 0.71 (s, 9H).

EXAMPLE 59

4-Oxo-2-phenyl-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid[(R)-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl]-amide.2-Phenyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one trifluoroacetate (55 mg,0.16 mmol) and(R)-7-amino-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(40 mg, 0.14 mmol) were reacted in a manner analogous to the preparationof 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.C18 preparatory HPLC afforded the title compound as white solid in 25%yield. High resolution MS m/e (M+H)⁺=542.2888.

EXAMPLE 60

Spiro[2,3-dihydro-1H-quinoline-2-one-4(1H), 4′piperidine]-1′-carboxylicacid[(R)-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl]-amide.Spiro[2,3-dihydro-1H-quinoline-2-one-4(1H),4′piperidine] (32 mg, 0.15mmol) and(R)-7-amino-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(35 mg, 0.12 mmol) were reacted in a manner analogous to the preparationof 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.C18 preparatory HPLC afforded the title compound as white solid in 46%yield. High resolution MS m/e (M+H)⁺=529.2924.

EXAMPLE 61

Spiro[2,3-dihydro-1H-isoquinoline-1-one-4(1H),4′piperidine]-1′-carboxylic acid[(R)-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl]-amide.Spiro[2,3-dihydro-1H-isoquinoline-1-one-4(1H),4′piperidine] (32 mg, 0.15mmol) and(R)-7-amino-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(35 mg, 0.12 mmol) were reacted in a manner analogous to the preparationof 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.C18 preparatory HPLC afforded the title compound as white solid in 41%yield. High resolution MS m/e (M+H)⁺=529.2927.

EXAMPLE 62

(R)-N-(9-(1-acetylpiperidin-4-yl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide.(R)-9-(1-acetylpiperidin-4-yl)-7-amino-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-onemethanesulfonate (42 mg, 0.08 mmol) and3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one acetate (30 mg, 0.10mmol) were reacted in a manner analogous to the preparation of4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.C18 preparatory HPLC afforded the title compound as white solid in 28%yield. High resolution MS m/e (M+H)⁺=599.3085.

EXAMPLE 63

4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-((R)-8-oxo-9-(pyrrolidin-3-yl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)piperidine-1-carboxamide.(R)-tert-butyl4-(8-oxo-7-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamido)-7,8-dihydroazepino[3,4-e]indazol-9(3H,6H,10H)-yl)piperidine-1-carboxylate(45 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL).Trifluoroacetic acid (0.25 mL)was added to the mixture. Reaction stirredat room temperature for 1.5 hour. Reaction mixture was concentrated invacuo. C18 preparatory HPLC purification afforded the title compound asyellow solid in 52% yield. High resolution MS m/e (M+H)⁺=543.2830.

EXAMPLE 64

(S)-9-neopentyl-7-(2-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.(S)-7-(2-hydroxyethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(15 mg, 0.04 mmol) was dissolved in dichloromethane (1 mL). Thionylchloride (100 μL) was added to the mixture. Reaction stirred at roomtemperature for 2 hours. Thionyl chloride (500 μL) was added to themixture. Reaction stirred at room temperature for 2 hours and then waswarmed to reflux for 2 hours. Reaction mixture was concentrated invacuo. Residue was dissolved in acetonitrile (1 mL). Potassium carbonate(25 mg, 0.18 mmol) was added to the mixture followed by3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (16 mg, 0.07 mmol).Reaction was heated at reflux for 2 hours. Preparatory HPLC purificationafforded the title compound as white solid in 25% yield. High resolutionMS m/e (M+H)⁺=529.3282.

EXAMPLE 65

(R)-N-(9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(3-phenylisoxazol-5-yl)piperidine-1-carboxamide.4-(3-Phenylisoxazol-5-yl)piperidine (46 mg, 0.20 mmol) and(R)-7-amino-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(110 mg, 0.22 mmol) were reacted in a manner analogous to thepreparation of4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.C18 preparatory HPLC afforded the title compound as tan solid in 33%yield. High resolution MS m/e (M+H)⁺=541.2916.

EXAMPLE 66

9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-aceticacid (75 mg, 0.23 mmol) and 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine (65 mg, 0.28 mmol) were combined in a manner analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as a white solid in 32% yield. Highresolution MS m/e (M+H)⁺=543.3084.

EXAMPLE 67

N-((R)-9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperidine-1-carboxamide.3-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (50 mg, 0.22 mmol) and(R)-7-amino-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(110 mg, 0.22 mmol) were reacted in a manner analogous to thepreparation of4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.C18 preparatory HPLC afforded the title compound as off-white solid in25% yield. High resolution MS m/e (M+H)⁺=543.3084.

EXAMPLE 68

N-((R)-9-Neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperazine-1-carboxamide.3-(Piperazin-1-yl)-3,4-dihydroquinolin-2(1H)-one (45 mg, 0.19 mmol) and(R)-7-amino-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(75 mg, 0.15 mmol) were reacted in a manner analogous to the preparationof 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.C18 preparatory HPLC afforded the title compound as white solid in 17%yield. High resolution MS m/e (M+H)⁺=544.3022.

EXAMPLE 69

(R)-N-(9-Neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxamide.2-(Piperidin-4-yl)-1,2-dihydroisoquinolin-3(4H)-one (60 mg, 0.26 mmol)and(R)-7-amino-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(100 mg, 0.20 mmol) were reacted in a manner analogous to thepreparation of4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide.C18 preparatory HPLC afforded the title compound as yellow solid in 29%yield. High resolution MS m/e (M+H)⁺=543.3074.

EXAMPLE 70

(S)-9-Neopentyl-7-(2-oxo-2-(4-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.2-(Piperidin-4-yl)-1,2-dihydroisoquinolin-3(4H)-one (105 mg, 0.46 mmol)and[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (110 mg, 0.33 mmol) were combined in a manner analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as a white solid in 40% yield. Highresolution MS m/e (M+H)⁺=541.3111.

EXAMPLE 71

1-[[7-(S)-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-spiro[piperidine-4,4′(1′H)-quinazolin]-2′(3′H)-one.Spiro[piperidine-4,4′(1¹H)-quinazolin]-2′(3′H)-one hydrochloride (50 mg,0.20 mmol) and[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (55 mg, 0.17 mmol) were combined in a manner analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 35% yield. High resolutionMS m/e (M+H)⁺=529.2921.

EXAMPLE 72

1-[[7-(S)-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(3-quinolinyl)piperidine.3-(piperidin-4-yl)quinoline (75 mg, 0.35 mmol) and[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (95 mg, 0.29 mmol) were combined in a manner analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as off-white solid in 50% yield. Highresolution MS m/e (M+H)⁺=522.2878.

EXAMPLE 73

1-[[7-(S)-4-choro-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(3-methoxy-2-naphthalenyl)piperidine.4-(3-Methoxynaphthalen-2-yl)piperidine hydrochloride (78 mg, 0.28 mmol)and[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (88 mg, 0.24 mmol) were combined in a manner analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Titlecompound was obtained as tan solid in 88% yield. An analytical samplewas prepared by C18 preparatory HPLC giving white solid with 30%recovery. High resolution MS m/e (M+H)⁺=587.2791.

EXAMPLE 74

1-[[7-(S)-4-choro-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(3-hydroxy-2-naphthalenyl)piperidine.A 1M solution of boron tribromide in dichloromethane (580 μL, 0.58 mmol)was added to a solution of1-[[7-(S)-4-choro-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(3-methoxy-2-naphthalenyl)piperidine(78 mg, 0.13 mmol) in dichloromethane (3 mL). Reaction stirred at roomtemperature for 4 hours. 1M Boron tribromide in dichloromethane (500 μL,0.5 mmol) was added to the mixture. Reaction stirred at room temperaturefor 30 minutes. Reaction mixture was concentrated in vacuo. Residue waspurified by C18 preparatory HPLC. Major peak was isolated. Methanol wasremoved from the combined fractions in vacuo. Remaining aqueous wasextracted with ethyl acetate (30 mL). Organic layer was washed withaqueous sodium bicarbonate (2×15 mL). Organic was dried (magnesiumsulfate), filtered and concentrated in vacuo. Title compound wasobtained as tan solid in 37% yield. High resolution MS m/e(M+H)⁺=573.2636.

EXAMPLE 75

1-[[(7S)-4-Chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethly)azepino[3,4-e]indazol-7-yl]acetyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-piperidine.[4-Chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (105 mg, 0.28 mmol) and 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)piperidine hydrochloride (85 mg, 0.32 mmol) were combined in a manneranalogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as pale yellow solid in 58% yield. Highresolution MS m/e (M+H)⁺=589.1932.

EXAMPLE 76

1-[[7-(S)-4-choro-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(3,4-dihydro-2,2-dioxido-4-oxo-1H-2,1-benzothiazin-3-yl)piperidine.2,2-Dioxo-3-piperidin-4-yl-2,3-dihydro-1H-2,1-benzothiazin-4-one (86 mg,0.27 mmol) and[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (85 mg, 0.23 mmol) were combined in a manner analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as tan solid in 37% yield. High resolutionMS m/e (M+H)⁺=626.2217.

EXAMPLE 77

1-[[7-(S)-4-choro-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(2,5-dioxo-3-phenyl-1-imidazolidinyl)piperidine.5-Phenyl-3-(piperidin-4-yl)imidazolidine-2,4-dione hydrochloride (46 mg,0.16 mmol) and[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (46 mg, 0.13 mmol) were combined in a manner analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as yellow solid in 67% yield. Highresolution MS m/e (M+H)⁺=605.2645.

EXAMPLE 78

1-[[7-(S)-4-choro-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(1,4-dihydro-2-oxopyrido[2,3-dipyrimidin-3(2H)-yl)-piperidine.3-(Piperidin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-onedihydrochloride (64 mg, 0.21 mmol) and[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (63 mg, 0.17 mmol) were combined in a manner analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 41% yield. High resolutionMS m/e (M+H)⁺=578.2630.

EXAMPLE 79

1-[[(7S)-4-chloro-9-(2,2-dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)-piperidine.3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one (57 mg, 0.19 mmol) and[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (60 mg, 0.16 mmol) were combined in a manner analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 64% yield. High resolutionMS m/e (M+H)⁺=575.2538.

EXAMPLE 80

1-[[(7S)-4-chloro-9-(2,2-dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(1,2-dihydro-2-oxo-1,6-naphthyridin-3-yl)-piperidine.3-(piperidin-4-yl)-1,6-naphthyridin-2(1H)-one (89 mg, 0.29 mmol) and[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (95 mg, 0.26 mmol) were combined in a manner analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 27% yield. High resolutionMS m/e (M+H)⁺=575.2538.

EXAMPLE 81

(S)-1-[[(7S)-4-chloro-9-(2,2-dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(2-oxido-3-isoquinolinyl)-piperidine.Title compound was prepared from 3-piperidin-4-ylisoquinolinehydrochloride in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as light brown solid. MS (ESI) 574 (M+H);R_(f)=2.39 (3 min gradient run).

EXAMPLE 82

(S)-]-[[(7S)-4-chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(4-pyridinylmethyl)azepino[3,4-e]indazol-7-yl]acetyl]-4-(2-oxido-3-isoquinolinyl)-piperidine.Title compound was prepared from 3-piperidin-4-ylisoquinolinehydrochloride in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid. MS (ESI) 595 (M+H); R_(f)=1.73 (3min gradient run).

EXAMPLE 83

(S)-1-[[(7S)-4-chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(4-pyridinylmethyl)azepino[3,4-e]indazol-7-yl]acetyl]-4-(1-oxido-5-phenyl-2-pyridinyl)-piperidine.Title compound was prepared from 5-phenyl-2-piperidin-4-ylpyridine1-oxide hydrochloride in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid. MS (ESI) 621 (M+H); R_(f)=1.87 (3min gradient run).

EXAMPLE 84

(S)-1-[[(7S)-4-chloro-9-(2,2-dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(1-oxido-5-phenyl-2-pyridinyl)-piperidine.Title compound was prepared from2-(piperidin-4-yl)-1,2-dihydroisoquinolin-3(4H)-one hydrochloride in amanner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid. MS (ESI) 600 (M+H); R_(f)=2.51 (3min gradient run).

EXAMPLE 85

(S)-4-chloro-7-(2-(4-(isoquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.Title compound was prepared from 3-(piperidin-4-yl)isoquinolinehydrochloride in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as white solid. MS (ESI) 579 (M+H); R_(f)=1.43 (3min gradient run).

EXAMPLE 86

(±)-1-[[(7S)-4-chloro-9-(2,2-dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]yacetyl]-Amino-3′,4′-dihydro-¹H-spiro[imidazolidine-4,2′naphthalene]-2,5-dione.Title compound was prepared from(±)-6′-Amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dionein a manner analogues to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as a white solid.

¹H-NMR (CD₃OD, 400 MHz) δ 0.78(s, 9H), 1.80-1.89 (m, 1H), 2.07-2.15(m,1H), 2.53 (dd, J=15.61, 5.04 Hz,1H), 2.76 (d, J=16.87 Hz, 1H), 2.92-3.18(m, 8H), 3.62-3.70 (m, 1H), 3.90-4.07 (m, 1H), 4.64 (d, J=17.37 Hz, 1H),5.47 (d, J=17.37 Hz,1H), 7.02 (d, J=8.31Hz, 1H), 7.21(s, 1H), 7.22-7.30(m, 1H), 7.35-7.45 (m 1H), 8.22 (d, J=2.52 Hz,1H); Mass spec.577.25(MH⁺), Calc. for C₃₀H₃₃ClN₆O₄ 576.23; R_(f)2.15 (4 min gradientrun).

EXAMPLE 87

(±)-1-[[(7S)-4-chloro-9-(2,2-dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-Amino-spiro[imidazolidine-4,2′-indane]-2,5-dione.Title compound was prepared from(±)-5′-Amino-spiro[imidazolidine-4,2′-indane]-2,5-dionein a manneranalogues to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Material was obtained as a white solid. ¹H-NMR (CD₃OD, 400 MHz) δ 0.79(s, 9H), 2.53 (dd, J=15.61,5.04 Hz, 1H), 2.92-3.3 (m, 6H), 3.46 (dd,J=16.49,9.44 Hz, 2H), 3.66 (d, J=13.60 Hz, 1H), 3.98-4.08 (m, 1H), 4.63(d, J=17.37 Hz, 1H), 5.47 (d, J=16.87 Hz,1H), 7.15 (d, J=8.06 Hz, 1H),7.21 (s, 1H), 7.25-7.35 (m, 1H), 7.50 (d, J=16.12 Hz, 1H), 8.23 (s, 1H);Mass spec. 563.24(MH⁺), Calc. for C₂₉H₃₁ClN₆O₄ 562.21; R_(f)=2.15 (4 mingradient run).

EXAMPLE 88

(E,Z)-N′-cyano-N-(9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamidine.To a solution of7-amino-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one,methanesulfonate (300 mg, 0.78 mmol) in CH₂Cl₂ (20 mL) was addeddiphenyl N-cyanocarbonimidate (221 mg, 0.93 mmol) followed bytriethylamine (1 mL). The reaction mixture was stirred at roomtemperature for 12 h. The reaction mixture was then washed with aqueoussodium hydrogencarbonate to give (E,Z)-1-cyano-3-(9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-2-phenylisoureain 95% yield. MS (ESI) 431 (M+H); R_(f)=2.22 (3 min gradient run).

To a solution of (E,Z)-1-cyano-3-(9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-2-phenylisourea(301 mg, 0.7 mmol) in isopropanol (25 mL) was added3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (323 mg, 1.4 mmol)and the reaction mixture was refluxed for 72 h. The solvent wasevaporated and the crude product was purified by flash chromatography togive (E,Z)-N′-cyano-N-(9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamidine(130 mg) in 33% yield. MS (ESI) 568 (M+H); R_(f)=2.19 (3 min gradientrun).

EXAMPLE 89

(S)-4-chloro-7-(2-oxo-2-(4-(2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (120 mg, 0.32 mmol) and3-(piperidin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-onedihydrochloride (120 mg, 0.40 mmol) were combined in a manner analogousto the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as pale yellow solid in 43% yield. Highresolution MS m/e (M+H)⁺=587.1785.

EXAMPLE 90

(S)-4-chloro-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (115 mg, 0.31 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride (96 mg, 0.36 mmol) were combined in a manner analogous tothe preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 65% yield. High resolutionMS m/e (M+H)⁺=586.1811.

EXAMPLE 91

(S)-4-chloro-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (115 mg, 0.31 mmol) and8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (96 mg, 0.36mmol) were combined in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 55% yield. High resolutionMS m/e (M+H)⁺=604.1760.

EXAMPLE 92

3-Piperidin-4-yl-1H-2,1-benzothiazine 2,2-dioxide p-toluenesulfonate (55mg, 0.13 mmol) and[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (40 mg, 0.11 mmol) were combined in a manner analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as tan solid in 57% yield. High resolutionMS m/e (M+H)⁺=610.2268.

EXAMPLE 93

(S)-4-chloro-7-(2-(4-(2,4-dichlorophenyl)piperidin-1-yl)-2-oxoethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.4-(2,4-Dichlorophenyl)-piperidine (32 mg, 0.0.8 mmol) and[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (25 mg, 0.07 mmol) were combined in a manner analogous to thepreparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as off-white solid in 40% yield. Highresolution MS m/e (M+H)⁺=575.1747.

EXAMPLE 94

(S)-4-bromo-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid (56 mg, 0.14 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride (35 mg, 0.15 mmol) were combined in a manner analogous tothe preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 61% yield. High resolutionMS m/e (M+H)⁺=618.2064.

EXAMPLE 95

(S)-4-bromo-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Bromo-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid (65 mg, 0.16 mmol) and8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (45 mg, 0.16mmol) were combined in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Titlecompound was obtained as white solid in 57% yield. High resolution MSm/e (M+H)⁺=636.1973.

EXAMPLE 96

(S)-4-bromo-7-(2-oxo-2-(4-(2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (69 mg, 0.16 mmol) and3-(piperidin-4-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-onedihydrochloride (120 mg, 0.40 mmol) were combined in a manner analogousto the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 55% yield. High resolutionMS m/e (M+H)⁺=631.1279.

EXAMPLE 97

(S)-4-bromo-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (73 mg, 0.17 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride (50 mg, 0.19 mmol) were combined in a manner analogous tothe preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as yellow solid in 62% yield. Highresolution MS m/e (M+H)⁺=630.1315.

EXAMPLE 98

(S)-4-bromo-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Bromo-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (80 mg, 0.19 mmol) and8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (61 mg, 0.22mmol) were combined in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as off-white solid in 64% yield. Highresolution MS m/e (M+H)⁺=648.1217.

EXAMPLE 99

(R)-7-Amino-4-chloro-9-(2,2-dimethyl-propyl)-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohept[e]inden-8-one(108 mg, 0.34 mmol) was dissolved in N,N-dimethylformamide (1.8 mL).N,N-Diisopropylethylamine (200 μL, 1.1 mmol) was added to the mixturefollowed by diphenyl cyanocarbonimidate (86 mg, 0.36 mmol). Mixture washeld at room temperature with stirring for 1.25 hours.3-(Piperidin-4-yl)quinolin-2(1H)-one hydrochloride (100 mg, 0.38 mmol)was added to the mixture with N,N-dimethylformamide (2.0 mL). Reactionwas warmed to 110° C. and held with stirring for 5.5 hours. Mixture wascooled to 80° C. and held with stirring for 20 hours. Reaction wasquenched with 1:1 acetonitrile:water. Material was purified bypreparatory HPLC (C18, acetonitrile-water-ammonium acetate). Major peakwas isolated. Acetonitrile was removed from the proper fractions invacuo. Material was extracted from the remaining aqueous twice withethyl acetate. Organic phase was dried (magnesium sulfate), filtered andconcentrated to dryness. Title compound was obtained as pale yellowsolid in 40% yield. High resolution MS m/e (M+H)⁺=599.2622.

EXAMPLE 100

(S)-4-methyl-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Methyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid (37 mg, 0.11 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride (32 mg, 0.12 mmol) were combined in a manner analogous tothe preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 55% yield. High resolutionMS m/e (M+H)⁺=554.3121.

EXAMPLE 101

(S)-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-4-methyl-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Methyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid (60 mg, 0.18 mmol) and8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (60 mg, 0.21mmol) were combined in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 48% yield. High resolutionMS m/e (M+H)⁺=572.3021.

EXAMPLE 102

(S)-4-methyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Methyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (65 mg, 0.18 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride (55 mg, 0.21 mmol) were combined in a manner analogous tothe preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 58% yield. High resolutionMS m/e (M+H)⁺=566.2364.

EXAMPLE 103

(S)-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-4-methyl-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Methyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (65 mg, 0.18 mmol) and8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (62 mg, 0.22mmol) were combined in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 53% yield. High resolutionMS m/e (M+H)⁺=584.2302.

EXAMPLE 104

(S)-4-isopropyl-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Isopropyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid (42 mg, 0.11 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride (36 mg, 0.14 mmol) were combined in a manner analogous tothe preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 33% yield. High resolutionMS m/e (M+H)⁺=582.3466.

EXAMPLE 105

(S)-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-4-isopropyl-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Isopropyl-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]-aceticacid (80 mg, 0.22 mmol) and8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (70 mg, 0.25mmol) were combined in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 60% yield. High resolutionMS m/e (M+H)⁺=600.3372.

EXAMPLE 106

(S)-4-isopropyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Isopropyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (50 mg, 0.13 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride (41 mg, 0.15 mmol) were combined in a manner analogous tothe preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 62% yield. High resolutionMS m/e (M+H)⁺=594.2682.

EXAMPLE 107

(S)-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-4-isopropyl-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Isopropyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (50 mg, 0.13 mmol) and8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (43 mg, 0.15mmol) were combined in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 66% yield. High resolutionMS m/e (M+H)⁺=612.2578.

EXAMPLE 108

(S)-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-4-(prop-1-en-2-yl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Isopropenyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (47 mg, 0.12 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride (42 mg, 0.16 mmol) were combined in a manner analogous tothe preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 55% yield. High resolutionMS m/e (M+H)⁺=592.2544.

EXAMPLE 109

(S)-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-4-(prop-1-en-2-yl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Isopropenyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (47 mg, 0.12 mmol) and8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (44 mg, 0.16mmol) were combined in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 60% yield. High resolutionMS m/e (M+H)⁺=610.2457.

EXAMPLE 110

(S)-4-ethyl-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[4-Ethyl-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethyl)-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]aceticacid (25 mg, 0.07 mmol) and8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (24 mg, 0.09mmol) were combined in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 49% yield. High resolutionMS m/e (M+H)⁺=598.2465.

EXAMPLE 111

(S)-4-bromo-9-(cyclopropylmethyl)-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-aceticacid (90 mg, 0.23 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride (80 mg, 0.30 mmol) were combined in a manner analogous tothe preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 32% yield. High resolutionMS m/e (M+H)⁺=602.1776.

EXAMPLE 112

(S)-4-bromo-9-(cyclopropylmethyl)-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-aceticacid (90 mg, 0.23 mmol) and8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (80 mg, 0.28mmol) were combined in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.

Title compound was obtained as white solid in 56% yield. High resolutionMS m/e (M+H)⁺=620.1665.

EXAMPLE 113

(S)-4-bromo-9-(2-methoxyethyl)-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid (100 mg, 0.25 mmol) and 3-(piperidin-4-yl)quinolin-2(1H)-onehydrochloride (80 mg, 0.30 mmol) were combined in a manner analogous tothe preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one.Title compound was obtained as white solid in 35% yield. High resolutionMS m/e (M+H)⁺=606.1730.

EXAMPLE 114

(S)-4-bromo-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-(2-methoxyethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.[(S)-4-Bromo-9-(2-methoxy-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl]-aceticacid (100 mg, 0.25 mmol) and8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (85 mg, 0.30mmol) were combined in a manner analogous to the preparation of4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10$$-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound wasobtained as white solid in 56% yield. High resolution MS m/e(M+H)⁺=624.1631.

EXAMPLE 115

¹H NMR (400 MHz, MeOD) δ ppm 0.79 (s, 9H), 1.45-1.52 (m, 2 H), 1.83-2.02(m, 2 H), 2.37-2.42 (m, 1 H), 2.68-2.76 (m, 1 H), 3.04-3.17 (m, 4 H),3.64-3.68 (m, 2 H), 3.92-4.06 (m, 1 H), 4.18-4.25 (m, 1 H), 4.63-4.74(m, 3 H), 5.46-5.54 (m, 1 H), 7.23 (s, 1 H), 7.12-7.23(m, 1 H),7.53-7.59 (m, 1 H), 7.75 (s, 1 H), 8.23 (s, 1H); Mass spec. 610.25(MH⁺), Calc. for C₃₂H₃₄ClF₂N₅O₃ 609.23.

EXAMPLE 116

¹H NMR (400 MHz, MeOD) δ ppm 0.80 (s, 9 H), 1.47-1.60 (m, 2H), 1.75-1.80(m, 1 H), 1.88-2.03 (m, 2 H), 2.32-2.48 (m, 1 H), 2.68-2.78 (m, 1 H),3.07-3.18 (m, 4 H), 3.66-3.68 (m, 1 H), 3.96-4.05 (m, 1 H), 4.13-4.24(m, 1 H), 4.53 (s, 2 H), 4.62-4.72 (m, 2 H), 5.45-5.60 (m, 1 H),7.17-7.24 (m, 1 H), 7.33 (s, 1H), 7.61 (d, J=8.31 Hz, 1 H), 7.75 (d,J=14.86 Hz, 1 H), 8.23 (s, 1 H); Mass spec. 608.23 (MH⁺), Calc. forC₃₂H₃₅Cl₂N₅O₃ 607.21.

EXAMPLE 117

¹H NMR (400 MHz, MeOD) δ ppm 0.79 (s, 9 H), 1.46-1.70(m, 2 H), 1.73-1.85(m, 1 H), 1.90-2.08 (m, 2 H), 2.36-2.51 (m, 1 H), 2.73-2.81 (m, 1 H),2.97-2.06 (s, 1 H), 3.09-3.20 (m, 4 H), 3.60-3.68 (m, 1 H), 3.95-4.08(s, 1 H), 4.21-4.27 (m, 1 H), 4.66-4.73 (m, 2 H), 5.46-5.54 (m, 1 H),7.15-7.23 (m, 2 H), 7.55-7.62 (m, 2 H), 7.79 (d, J=15.86 Hz, 1H), 8.23(s, 1H); Mass spec. 608.26 (MH⁺), Calc. for C₃₂H₃₅Cl₂N₅O₃ 607.21.

EXAMPLE 118

¹H NMR (400 MHz, MeOD) δ ppm 0.80 (s, 9 H), 1.46-1.56 (m, 1 H),1.57-1.74 (m, 1 H), 1.80-2.08 (m, 2 H), 2.35-2.50 (m, 1 H), 2.69-2.80(m, 1 H), 2.89-3.04 (m, 1 H), 3.09-3.20 (m, 4 H), 3.63 (dd, J=19.14,13.85 Hz, 1 H), 3.95-4.07 (m, 1 H), 4.20-4.32 (m, 1 H), 4.60-4.72 (m, 3H), 5.47 (d, J=19.14 Hz, 1 H), 6.88-6.96 (m, 1 H), 7.12 (t, J=8.94 Hz, 1H), 7.22 (s, 1 H), 7.39-7.47 (m, 1 H), 7.88 (d, J=21.66 Hz, 1 H), 8.23(s, 1 H); Mass spec. 592.28 (MH⁺), Calc. for C₃₂H₃₅ClFN₅O₃ 591.24.

EXAMPLE 119

¹H NMR (400 MHz, MeOD) δ ppm 0.79 (s, 9 H), 1.45-1.66 (m, 2 H),1.70-1.83 (m, 1 H), 1.90-2.07 (m, 2 H), 2.38-2.50 (m, 1 H), 2.69-2.80(m, 1 H), 2.92-3.18 (m, 4 H), 3.60-3.69 (m, 1 H), 3.95-4.07 (m, 1 H),4.18-4.32(m, 1 H), 4.56-4.69 (m, 3 H), 5.43-5.58 (m, 1 H), 6.41 (s, 1H), 7.23 (s, 1 H), 7.64-7.70 (m, 1 H), 7.80-7.84(m, 1 H), 8.23 (s, 1 H);Mass spec. 593.25 (MH⁺), Calc. for C₃₁H₃₄ClFN₆O₃ 592.24.

EXAMPLE 120

¹H NMR (400 MHz, MeOD) δ ppm 0.79 (s, 9 H), 1.45-1.68 (m, 2 H),1.71-1.82 (m, 1 H), 1.90-2.07 (m, 2 H), 2.37-2.49 (m, 1 H), 2.68-2.79(m, 1 H), 2.92-3.18 (m, 4 H), 3.59-3.68 (m, 1 H), 3.94-4.06 (m, 1 H),4.17-4.30(m, 1 H), 4.55-4.68 (m, 3 H), 5.43-5.58 (m, 1 H) 6.95-7.04 (m,2 H) 7.22 (s, 1 H) 7.61-7.68 (m, 1 H) 7.75 (d, J=14.60 Hz, 1 H) 8.23 (s,1 H); Mass spec. 592.28 (MH⁺), Calc. for C₃₂H₃₅ClFN₅O₃ 592.24.

EXAMPLE 121

(R)-N-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-N′-cyano-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamidine.(R)-7-Amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(130 mg, 390.7 μmol) was dissolved in N,N-dimethylformamide (5.0 mL).N,N-Diisopropylethylamine (200 μL, 1.1 mmol) was added to the mixturefollowed by diphenyl N-cyanocarbonimidate (100 mg, 407.1 μmol). Mixturestirred at room temperature for 40 minutes.3-(Piperidin-4-yl)quinolin-2(1H)-one hydrochloride (125 mg; 472.1 μmol)was added to the vessel with stirring. The mixture was heated to 100° C.and held for 54 hr with stirring. Mixture was cooled to room temperatureand then diluted with methanol. Mixture was filtered. Filtrate waspurified by reverse phase prep HPLC (acetonitrile-water-ammoniumacetate). Acetonitrile was removed from the fractions by roto-vap.Remaining aqueous was diluted with water. Solids were filtered off andwashed with water. Air was pulled through the filter cake for 2 hours.Solids were collected and then dried in vacuo. Title compound wasobtained as tan solid in 33% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm13.62 (s, 1 H) 11.79 (s, 1 H) 8.35 (s, 1H) 7.73 (s, 1 H) 7.66 (d, J=7.94Hz, 1H) 7.53 (d, J=7.93 Hz, 1H) 7.44 (t, J=7.63 Hz, 1 H) 7.25-7.33 (m, 2H) 7.16 (t, J=7.48 Hz, 1 H) 5.59-5.71 (m, 1 H) 5.40 (d, J=17.40 Hz, 1 H)4.90 (d, J=17.70 Hz, 1 H) 4.59-4.77 (m, 1 H) 4.27 (d, J=13.12 Hz, 2H)4.00-4.15 (m, 1 H) 3.33-3.42 (m, 1 H) 3.03-3.26 (m, 4 H) 1.86-1.98 (m,2) 1.54-1.71 (m, 2 H). High resolution MS m/e (M+H)⁺=611.1890.

EXAMPLE 122

(R)-N-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-N′-cyano-4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamidine.(R)-7-Amino-4-chloro-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(115 mg, 345.6 mmol) was dissolved in N,N-dimethylformamide (5.0 mL).N,N-Diisopropylethylamine (200 μL, 1.1 mmol) was added to the mixturefollowed by diphenyl N-cyanocarbonimidate (94 mg, 382.7 μmol). Mixturestirred at room temperature for 40 minutes.8-Fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (121 mg,427.9 μmol) was added to the vessel with stirring. The mixture washeated to 60° C. and held with stirring for 54 hours. The mixture waswarmed to 100° C. and with stirring held for 28 hours. Reaction wasdiluted with methanol. Mixture was purified by prep HPLC(acetonitrile-water-ammonium acetate). Acetonitrile was removed from thefractions by roto-vap. Remaining aqueous was diluted with water. Solidswere filtered off and washed with water. Air was pulled through thefilter cake for 1 hour. Solids were collected and dried in vacuo. Titlecompound was obtained as tan solid in 34% yield. 1H NMR (500 MHz,DMSO-D6) δ ppm 13.61 (s, 1 H) 11.82 (s, 1 H) 8.35 (s, 1 H) 7.80 (s, 1 H)7.52 (dd, J=16.48, 7.63 Hz, 2 H) 7.32-7.39 (m, 1 H) 7.29 (s, 1 H)7.08-7.19 (m, 1 H) 5.57-5.76 (m, 1 H) 5.40 (d, J=18.01 Hz, 1 H) 4.90 (d,J=17.40 Hz, 1 H) 4.59-4.79 (m, 1 H) 4.27 (d, J=12.82 Hz, 2 H) 4.01-4.17(m, 1 H) 3.32-3.41 (m, 1 H) 2.98-3.25 (m, 4 H) 1.78-2.00 (m, 2 H)1.42-1.71 (m, 2 H). High resolution MS m/e (M+H)⁺=629.1788.

EXAMPLE 123

(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate.(R)-4-chloro-7-hydroxy-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(60.0 mg, 0.180 mmol) in THF (10.0 mL, 122 mmol) was added sodiumhydride (10.79 mg, 0.450 mmol) followed by 4-nitrophenyl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (106 mg,0.270 mmol). After stirring for 48 h, most of the solvent was removed,diluted with dichloromethane (30 mL) and neutralized with 1.0 M HCl. Theorganic phase was separated, dried (Na₂SO₄) and the crude product waspurified by flash chromatography using 5% MeOH in dichloromethane togive(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate (38.00 mg,0.065 mmol, 36% yield). MS (ESI) 588 (M+H); R_(f)=2.73.

EXAMPLE 124

(S)-4-chloro-7-(2-oxo-2-(2′-oxo-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinazoline]-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one.To a solution of(S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)aceticacid (50 mg, 0.133 mmol) in dichloromethane (25 mL) was added1′H-spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one (31 mg, 0.14 mmol)followed by 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (47 mg, 0.15 mmol) and triethylamine (1.0 mL). After12 h, the reaction mixture was washed with aqueous NaHCO₃ followed by1.0 M HCl and dried (Na₂SO₄). The solvent was removed and the crudeproduct was purified by flash chromatography using 7% MeOH indichloromethane to give(S)-4-chloro-7-(2-oxo-2-(2′-oxo-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinazoline]-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one(61 mg, 79%) as awhite powder. MS (ESI) 575 (M+H); R_(f)=2.133.

1. A compound of selected from the group consisting of4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(9-benzyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-amide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(9-methyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-amide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-piperidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-pyrrolidin-1-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[9-(2-dimethylamino-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide;5-Neopentyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)ethyl)-7,8-dihydro-1H-pyrazolo[3,4-g]quinolin-6(5H)-one;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[9-(2-morpholin-4-yl-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide;′H-Spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one-1-carboxylic acid[9-(2-morpholin-4-yl-ethyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide;′H-Spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one-1-carboxylic acid[8-oxo-9-(1-(S)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(1-(S)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(1-(R)-phenyl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(9-benzyl-4-chloro-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-amide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(4-trifluoromethyl-benzyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide;′H-spiro[piperidine-4,4′-quinazolin]-2′(3′H)-one-1-carboxylic acid[8-oxo-9-(4-trifluoromethyl-benzyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(9-isopropyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-amide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[9-(3,3-dimethyl-butyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide;4-(8-Oxo-7-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-6,7,8,10-tetrahydro-3H-2,3,9-triaza-(R)-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylicacid tert-butyl ester;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(8-oxo-9-piperidin-4-yl-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl)-amide;9-(2,2-Dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-amide;4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl]-amide;N-[9-(2,2-dimethylpropyl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]-2′-oxo-2′,3′-dihydro-1H,1′H-spiro[piperidine-4,4′-quinazoline]-1-carboxamide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(9-isobutyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-amide;N-[9-(2-methylpropyl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]-2′-oxo-2′,3′-dihydro-1H,1′H-spiro[piperidine-4,4′-quinazoline]-1-carboxamide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid[8-oxo-9-(2-pyridin-4-yl-ethyl)-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl]-amide;N-[9-(2-pyridin-4-yl-ethyl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]-2′-oxo-2′,3′-dihydro-1H,1′H-spiro[piperidine-4,4′-quinazoline]-1-carboxamide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(8-oxo-9-pyridin-4-ylmethyl-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-amide;N-[9-pyridin-4-ylmethyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl]-2′-oxo-2′,3′-dihydro-1H,1′H-spiro[piperidine-4,4′-quinazoline]-1-carboxamide;4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carboxylic acid(4,9-dimethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-amide;(S)-4-Chloro-7-(2-oxo-2-(4-(5-phenyl-1H-pyrazol-3-yl)piperidin-1-yl)ethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-9-Neopentyl-7-(2-oxo-2-(4-(2-oxo-4-phenyl-2,3-dihydroimidazol-1-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(R)-N-(8-Benzyl-7-oxo-1,5,6,7,8,9-hexahydroazepino[4,3-f]indazol-6-yl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide;(S)-9-Benzyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-7-(2-(4-(8-Fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)-2-oxoethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)-2-oxoethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-9-neopentyl-7-(2-oxo-2-(4-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-9-Neopentyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-4-phenyl-2,3-dihydroimidazol-1-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-4-(pyridin-2-yl)-2,3-dihydroimidazol-1-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-1′H-spiro(piperidine-4,4′-quinazoline)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-9-neopentyl-7-(2-oxo-2-(4-(3-oxo-3,4-dihydroquinoxalin-2-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)ethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)-2-oxoethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-Chloro-7-(2-oxo-2-(4-(2-oxo-4-phenyl-2,3-dihydroimidazol-1-yl)piperidin-1-yl)ethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-9-((1H-Imidazol-2-yl)methyl)-4-chloro-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;N-((R)-9-Benzyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperidine-1-carboxamide;(7S)-9-Benzyl-7-(2-oxo-2-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperazin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;4-Oxo-2-phenyl-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid[(R)-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl]-amide;Spiro[2,3-dihydro-1H-quinoline-2-one-4(1H),4′piperidine]-1′-carboxylicacid[(R)-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl]-amide;Spiro[2,3-dihydro-1H-isoquinoline-1-one-4(1H),4′piperidine]-1′-carboxylicacid[(R)-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl]-amide;(R)-N-(9-(1-acetylpiperidin-4-yl)-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide;4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)-N-((R)-8-oxo-9-(pyrrolidin-3-yl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)piperidine-1-carboxamide;(S)-9-neopentyl-7-(2-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(R)-N-(9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(3-phenylisoxazol-5-yl)piperidine-1-carboxamide;9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one;N-((R)-9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperidine-1-carboxamide;N-((R)-9-Neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)piperazine-1-carboxamide;(R)-N-(9-Neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-carboxamide;(S)-9-Neopentyl-7-(2-oxo-2-(4-(3-oxo-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;1-[[7-(S)-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-spiro[piperidine-4,4′(1′H)-quinazolin]-2′(3′H)-one;1-[[7-(S)-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(3-quinolinyl)piperidine;1-[[7-(S)-4-choro-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(3-methoxy-2-naphthalenyl)piperidine;1-[[7-(S)-4-choro-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(3-hydroxy-2-naphthalenyl)piperidine;1-[[(7S)-4-Chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(2,2,2-trifluoroethly)azepino[3,4-e]indazol-7-yl]acetyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-piperidine;1-[[7-(S)-4-choro-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(3,4-dihydro-2,2-dioxido-4-oxo-1H-2,1-benzothiazin-3-yl)piperidine;1-[[7-(S)-4-choro-9-(2,2-Dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(2,5-dioxo-3-phenyl-1-imidazolidinyl)piperidine;1-[[7-(S)-4-choro-9-(2,2-Di-methylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(1,4-dihydro-2-oxopyrido[2,3-d]pyrimidin-3(2H)-yl)-piperidine;1-[[(7S)-4-chloro-9-(2,2-dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl)-piperidine;1-[[(7S)-4-chloro-9-(2,2-dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(1,2-dihydro-2-oxo-1,6-naphthyridin-3-yl)-piperidine;(S)-1-[[(7S)-4-chloro-9-(2,2-dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(2-oxido-3-isoquinolinyl)-piperidine;(S)-1-[[(7S)-4-chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(4-pyridinylmethyl)azepino[3,4-e]indazol-7-yl]acetyl]-4-(2-oxido-3-isoquinolinyl)-piperidine;(S)-1-[[(7S)-4-chloro-3,6,7,8,9,10-hexahydro-8-oxo-9-(4-pyridinylmethyl)azepino[3,4-e]indazol-7-yl]acetyl]-4-(1-oxido-5-phenyl-2-pyridinyl)-piperidine;(S)-1-[[(7S)-4-chloro-9-(2,2-dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-4-(1-oxido-5-phenyl-2-pyridinyl)-piperidine;(S)-4-chloro-7-(2-(4-(isoquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-(pyridin-4-ylmethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(±)-1-[[(7S)-4-chloro-9-(2,2-dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-Amino-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione;(±)-1-[[(7S)-4-chloro-9-(2,2-dimethylpropyl)-3,6,7,8,9,10-hexahydro-8-oxoazepino[3,4-e]indazol-7-yl]acetyl]-Amino-spiro[imidazolidine-4,2′-indane]-2,5-dione;(E,Z)-N′-cyano-N-(9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamidine;(S)-4-chloro-7-(2-oxo-2-(4-(2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-chloro-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-chloro-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-chloro-7-(2-(4-(2,4-dichlorophenyl)piperidin-1-yl)-2-oxoethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-bromo-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-bromo-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-bromo-7-(2-oxo-2-(4-(2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-bromo-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-bromo-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-methyl-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-4-methyl-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-methyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-4-methyl-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-isopropyl-9-neopentyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-4-isopropyl-9-neopentyl-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-isopropyl-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-4-isopropyl-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-4-(prop-1-en-2-yl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-4-(prop-1-en-2-yl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-ethyl-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-bromo-9-(cyclopropylmethyl)-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-bromo-9-(cyclopropylmethyl)-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-bromo-9-(2-methoxyethyl)-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(S)-4-bromo-7-(2-(4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidin-1-yl)-2-oxoethyl)-9-(2-methoxyethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;(R)-N-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-N′-cyano-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamidine;(R)-N-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)-N′-cyano-4-(8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamidine;(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxylate; and(S)-4-chloro-7-(2-oxo-2-(2′-oxo-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinazoline]-1-yl)ethyl)-9-(2,2,2-trifluoroethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3H)-one;or a pharmaceutically acceptable salt thereof.
 2. A compound selectedfrom the group consisting of

or a pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable adjuvant,carrier, or diluent.
 4. A pharmaceutical composition comprising acompound of claim 2, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable adjuvant, carrier, or diluent.
 5. A methodof treating migraine comprising the administration of a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, to a patient.
 6. A method of treating migrainecomprising the administration of a therapeutically effective amount of acompound of claim 2, or a pharmaceutically acceptable salt thereof, to apatient.